Substituted pyrazolo[1,5-a]pyrimidines as inhibitors of metabotropic glutamate receptors

ABSTRACT

The present invention relates to novel pyrazolo- and imidazo-pyrimidine derivatives of formula I 
                         
wherein A, D, E, L, M, Q, R 1 , R 2  and R 3  are as defined hereinabove. The present invention also relates to a process for their preparation, a pharmaceutical composition containing said derivatives and a method of treating or preventing acute or chronic neurological disorder comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one such derivatives. These disorders include acute and chronic disorders.

PRIORITY TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 10/948,970,filed Sep. 24, 2004, now pending; which claims the benefit of EuropeanApplication No. 03078075.3, filed Oct. 3, 2003.

FIELD OF THE INVENTION

The present invention relates to a compound of formula I

-   wherein A, D, E, L, M, Q, R¹, R² and R³ are described hereinbelow,    or a pharmaceutically acceptable salt thereof. This invention also    relates to a pharmaceutical composition comprising the pyrazolo- and    imidazo-pyrimidine derivatives of formula I, a process for preparing    the compound of formula I and a method of treating or preventing    acute or chronic neurological disorders comprising administering to    a patient in need of such treatment a therapeutically effective    amount of said pharmaceutical composition. These disorders include    acute and chronic disorders

BACKGROUND OF THE INVENTION

In the central nervous system (CNS), the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain andplays a unique role in a variety of central nervous system (CNS)functions. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group, namely the ionotropic receptors,forms ligand-controlled ion channels. The metabotropic glutamatereceptors (mGluR) belong to the second main group and, furthermore,belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR are known and ofthese some even have sub-types. According to their sequence homology,signal transduction mechanisms and agonist selectivity, these eightreceptors can be sub-divided into three sub-groups:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to groupII and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first groupcan be used for the treatment or prevention of acute and/or chronicneurological disorders such as psychosis, epilepsy, schizophrenia,Alzheimer's disease, cognitive disorders and memory deficits, as well aschronic and acute pain.

Other treatable indications in this connection are restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are ischemia, Huntington's chorea, amyotrophic lateralsclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy,idiopathic parkinsonism or parkinsonism caused by pharmaceuticalpreparations, i.e., medicaments, as well as conditions which lead toglutamate-deficiency functions, such as e.g. muscle spasms, convulsions,migraine, urinary incontinence, nicotine addiction, opiate addiction,anxiety, vomiting, dyskinesia and depressions.

Disorders mediated full or in part by mGluR2 are for example acute,traumatic and chronic degenerative processes of the nervous system, suchas Alzheimer's disease, senile dementia, Parkinson's disease,Huntington's chorea, amyotrophic lateral sclerosis and multiplesclerosis, psychiatric diseases such as schizophrenia and anxiety,depression, pain, drug dependency, smoking cessation und ethanoldependence (Expert Opin. Ther. Patents (2002), 12, (12), 3537-3541).

Selective mGluR2 antagonists are especially useful for the treatment ofanxiety and pain.

SUMMARY OF THE INVENTION

This invention relates to a compound of formula 1

-   wherein-   A is ═C(R⁴)—,-   D is ═C(R⁵)—,-   E is ═C(R⁶)—,-   or one of A, D and E is ═N—,-   L is ═N— or ═C(H)—,-   M is ═C(R⁷)—, when L is ═N—, or M is ═N—, when L is ═C(H)—,-   Q is CF₃ of CHF₂,-   R¹ is selected from —CN, unsubstituted pyridinyl, pyridinyl    substituted by (C₁-C₄)-alkyl, pyridinyl substituted by    (C₁-C₄)-alkanol, and corresponding pyridine-N-oxide of unsubstituted    pyridinyl, pyridinyl substituted by (C₁-C₄)-alkyl, pyridinyl    substituted by (C₁-C₄)-alkanol,-   R² is selected from hydrogen, halogen, (C₁-C₄)-alkyl and    (C₃-C₆)-cycloalkyl,-   R³ is selected from hydrogen, halogen, (C₁-C₄)-alkyl and    (C₃-C₆)-cycloalkyl,-   R⁴ is selected from hydrogen, halogen, unsubstituted (C₁-C₄)-alkyl,    (C₁-C₄)-alkyl substituted by fluorine, unsubstituted (C₁-C₄)-alkoxy,    (C₁-C₄)-alkoxy substituted by fluorine, unsubstituted    (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted by fluorine,-   R⁵ is selected from hydrogen, halogen, unsubstituted (C₁-C₄)-alkyl,    (C₁-C₄)-alkyl substituted by fluorine, unsubstituted    (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted by fluorine,-   R⁶ is hydrogen or halogen, and-   R⁷ is selected from hydrogen, unsubstituted (C₁-C₄)-alkyl,    (C₁-C₄)-alkyl substituted by CN, unsubstituted (C₃-C₆)-cycloalkyl    and (C₃-C₆)-cycloalkyl substituted by CN,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and (a) M is    ═C(H)—, R⁴ is not selected from hydrogen, chloro or methoxy; or (b)    M is ═C(CH₃)—, R⁴ is not hydrogen,    or a pharmaceutically acceptable salt thereof.

Another embodiment of this invention is related to a process forpreparing a compound of formula I. Another embodiment of this inventionis related to a pharmaceutical composition containing a compound offormula I and a pharmaceutically acceptable excipient. Yet anotherembodiment of this invention is related to a method of treatment orprevention of mGluR2 receptor mediated disorders.

DETAILED DESCRIPTION OF THE INVENTION

The following description of general terms used in the presentdescription apply irrespective of whether the term in question appearalone or in combination.

Examples for alkyl include straight chain and branched saturated carbonchains containing from one to 4 carbon atoms, e.g. methyl, ethyl, andthe isomers of propyl and butyl, e.g. isopropyl and tert-butyl. Examplesfor substituted alkyl include CF₃ and CH₂CN. An example for alkoxy isethoxy. An example for substituted ethoxy is OCH₂CF₃. Examples forcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Examples for pyridinyl are pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.Examples for substituted pyridinyl are methylpyridinyl,dimethylpyridinyl, hydroxymethylpyridinyl and methyloxypyridinyl, e.g.2-methylpyridinyl, 2,6-dimethylpyridinyl, 2-hydroxymethylpyridinyl and2-methyl-1-oxypyridinyl, e.g. 2-methylpyridin-4-yl,2,6-dimethylpyridin-4-yl, 2-hydroxymethylpyridin-4-yl and2-methyl-1-oxypyridin-4-yl.

Examples for halogen are chlorine and fluorine.

Unless otherwise specified, the term “alkanol” as defined thereindenotes an alkyl radical having 1 to 10 carbon atoms, preferably 1 to 6and still more preferably 1 to 4 carbon atoms as defined above, which issubstituted by one, two or three, preferably one, hydroxyl group(s).Examples of alkanols include methanol, ethanol, n-propan-2-ol,n-propan-3-ol, isopropanol, i-butanol and those specifically exemplifiedin the instant application among the examples.

The term “pharmaceutically acceptable salt” refers to any salt derivedfrom an inorganic or organic acid or base. Examples include thehydrochloride, sulfate, fumarate, mesylate, phosphate, maleate andtartrate salts. Such salts may be prepared according to common andgeneral methods known by the person skilled in the art.

The term “pharmaceutically acceptable excipient” refers to apharmaceutically acceptable carrier, vehicle, diluent, adjustment orsimilar mechanism for delivering a pharmaceutical composition.

The term therapeutically effective amount” refers to an amount of atleast one compound of formula I, or a pharmaceutically acceptable saltthereof, that modulates metabotropic glutamate receptors, includingmGluR2.

In one embodiment, this invention relates to a compound of formula I,wherein:

-   A is ═C(R⁴)—,-   D is ═C(R⁵)—,-   E is ═C(R⁶)—,    or one of A, D and E is ═N—,-   L is ═N— or ═C(H)—,-   M is ═C(R⁷)—, when L is ═N—, or M is ═N—, when L is ═C(H)—,-   Q is CF₃,-   R¹ is selected from —CN, unsubstituted pyridinyl, pyridinyl    substituted by (C₁-C₄)-alkyl and corresponding pyridine-N-oxide of    pyridinyl substituted by (C₁-C₄)-alkyl,-   R² is selected from hydrogen, halogen, (C₁-C₄)-alkyl and    (C₃-C₆)-cycloalkyl,-   R³ is selected from hydrogen, halogen, (C₁-C₄)-alkyl and    (C₃-C₆)-cycloalkyl,-   R⁴ is selected from hydrogen, halogen, unsubstituted (C₁-C₄)-alkyl,    (C₁-C₄)-alkyl substituted by fluorine, unsubstituted (C₁-C₄)-alkoxy,    (C₁-C₄)-alkoxy substituted by fluorine, unsubstituted    (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted by fluorine,-   R⁵ is selected from hydrogen, halogen, unsubstituted (C₁-C₄)-alkyl,    (C₁-C₄)-alkyl substituted by fluorine, unsubstituted    (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted by fluorine,-   R⁶ is hydrogen or halogen, and-   R⁷ is selected from hydrogen, unsubstituted (C₁-C₄)-alkyl,    (C₁-C₄)-alkyl substituted by CN, unsubstituted (C₃-C₆)-cycloalkyl    and (C₃-C₆)-cycloalkyl substituted by CN,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and (a) M is    ═C(H)—, R⁴ is not selected from hydrogen, chloro and methoxy; or (b)    M is ═C(CH₃)—, R⁴ is not hydrogen,-   and their pharmaceutically acceptable addition salts.

In another embodiment, the present invention provides a compound offormula I wherein A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen,halogen, unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted byfluorine, unsubstituted (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxy substituted byfluorine, unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkylsubstituted by fluorine. In another embodiment, the invention provides acompound of formula I wherein A is ═C(R⁴)—, wherein R⁴ is selected fromhydrogen, Cl, F, CH₃, CF₃, OCH₃, OCH₂CH₃ and OCH₂CF₃. In still anotherembodiment, the invention provides a compound of formula I wherein A is═C(R⁴)—, wherein R⁴ is CF₃.

In another embodiment, the present invention provides a compound offormula I wherein D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen,halogen, unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted byfluorine, unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkylsubstituted by fluorine. In another embodiment, the invention provides acompound of formula I wherein D is ═C(R⁵)—, wherein R⁵ is selected fromhydrogen, Cl, F, CH₃ and CF₃. In still another embodiment, the inventionprovides a compound of formula I wherein D is ═C(R⁵)—, wherein R⁵ isselected from hydrogen, F and CH₃.

In another embodiment, the present invention provides a compound offormula I wherein E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen. Inanother embodiment, the invention provides a compound of formula Iwherein E is ═C(R⁶)—, wherein R⁶ is hydrogen. In one embodiment, thepresent invention provides a compound of formula I wherein L is ═N—. Inanother embodiment, the invention provides a compound of formula Iwherein L is ═C(H)—.

In another embodiment, the present invention provides a compound offormula I wherein M is ═C(R⁷)—, wherein R⁷ is selected from hydrogen,unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by CN,unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted byCN. In another embodiment, the invention provides a compound of formulaI wherein M is ═C(R⁷)—, wherein R⁷ is hydrogen. In still anotherembodiment, the invention provides a compound of formula I wherein M is═C(R⁷)—, wherein R⁷ is unsubstituted (C₁-C₄)-alkyl or (C₁-C₄)-alkylsubstituted by CN. In still another embodiment, the present inventionprovides a compound of formula I wherein M is ═C(R⁷)—, wherein R⁷ is CH₃or CH₂CN. In another embodiment, the present invention provides acompound of formula I wherein M is ═N—.

In another embodiment, the present invention provides a compound offormula I wherein R¹ is —CN. In another embodiment, the inventionprovides a compound of formula I wherein R¹ is selected fromunsubstituted pyridinyl, pyridinyl substituted by (C₁-C₄)-alkyl and thecorresponding pyridine-N-oxide of pyridinyl substituted by(C₁-C₄)-alkyl. In still another embodiment, the invention provides acompound of formula I wherein R¹ is selected from pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, methylpyridin-4-yl, dimethylpyridin-4-yl,hydroxymethylpyridin-4-yl and methyloxypyridin-4-yl. In still anotherembodiment, the invention provides a compound of formula I wherein R¹ isselected from pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl,2,6-dimethylpyridin-4-yl, 2-hydroxymethylpyridin-4-yl and2-methyl-1-oxy-pyridin-4-yl. In still another embodiment, the inventionprovides a compound of formula I wherein R¹ is selected frompyridin-4-yl, 2-methylpyridin-4-yl and 2,6-dimethylpyridin-4-yl.

In one embodiment, the present invention provides a compound of formulaI wherein R² is hydrogen.

In one embodiment, the present invention provides a compound of formulaI wherein R³ is hydrogen.

In another embodiment, the present invention provides a compound offormula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxy substituted by    fluorine, unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl    substituted by fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted    by fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═N— or ═C(H)—,-   M is ═C(R⁷)—, wherein R⁷ is selected from hydrogen, unsubstituted    (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by CN, unsubstituted    (C₃-C₆)-cycloalkyl, and (C₃-C₆)-cycloalkyl substituted by CN, when L    is ═N—; or M is ═N—, when L is ═C(H)—,-   R¹ is selected from —CN, unsubstituted pyridinyl, pyridinyl    substituted by (C₁-C₄)-alkyl, and the corresponding pyridine-N-oxide    of pyridinyl substituted by (C₁-C₄)-alkyl,-   R² is selected from hydrogen, halogen, (C₁-C₄)-alkyl and    (C₃-C₆)-cycloalkyl,-   R³ is selected from hydrogen, halogen, (C₁-C₄)-alkyl and    (C₃-C₆)-cycloalkyl,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and (a) M is    ═C(H)—, R⁴ is not selected from hydrogen, chloro and methoxy; or (b)    M is ═C(CH₃)—, R⁴ is not hydrogen.

In another embodiment, the present invention provides a compound offormula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxy substituted by    fluorine, unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl    substituted by fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted    by fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is selected from hydrogen, unsubstituted    (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by CN, unsubstituted    (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted by CN,-   R¹ is selected from —CN, unsubstituted pyridinyl, pyridinyl    substituted (C₁-C₄)-alkyl, and the corresponding pyridine-N-oxide of    pyridinyl substituted (C₁-C₄)-alkyl,-   R² is selected from hydrogen, halogen and (C₁-C₄)-alkyl,-   R³ is selected from hydrogen, halogen and (C₁-C₄)-alkyl,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and (a) M is    ═C(H)—, R⁴ is not selected from hydrogen, chloro and methoxy; or (b)    M is ═C(CH₃)—, R⁴ is not hydrogen.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxy substituted by    fluorine, unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl    substituted by fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted    by fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is selected form hydrogen, unsubstituted    (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by CN, unsubstituted    (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted by fluorine,-   R¹ is —CN,-   R² is selected from hydrogen, halogen and (C₁-C₄)-alkyl,-   R³ is selected from hydrogen, halogen and (C₁-C₄)-alkyl,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and (a) M is    ═C(H)—, R⁴ is not selected from hydrogen, chloro and methoxy; or (b)    M is ═C(CH₃)—, R⁴ is not hydrogen.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by    fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is selected from hydrogen, unsubstituted    (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by CN,-   R¹ is —CN, and-   R² and R³ are hydrogen,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and M is ═C(H)—,    R⁴ is not selected from hydrogen, chloro and methoxy.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by    fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is hydrogen,-   R¹ is —CN, and-   R² and R³ are hydrogen,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and M is ═C(H)—,    R⁴ is not selected from hydrogen, chloro and methoxy.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by    fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is hydrogen,-   R¹ is —CN, and-   R² and R³ are hydrogen,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and M is ═C(H)—,    R⁴ is not selected from hydrogen, chloro and methoxy.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, Cl, F, methyl,    trifluoromethyl and 2-trifluoroethoxy,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, Cl, F, methyl    and trifluoromethyl,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is hydrogen,-   R¹ is —CN, and-   R² and R³ are hydrogen,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and M is ═C(H)—,    R⁴ is selected from not hydrogen, chloro and methoxy.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by    fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is unsubstituted (C₁-C₄)-alkyl or    (C₁-C₄)-alkyl substituted by CN,-   R¹ is —CN, and-   R² and R³ are hydrogen,-   with the proviso that when A is ═C(R⁴)—, D is ═C(H)—, E is ═C(H)—, L    is ═N—, R¹ is —CN, R² is hydrogen, R³ is hydrogen, and M is    ═C(CH₃)—, R⁴ is not hydrogen.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by    fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is selected from hydrogen, unsubstituted    (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by CN-   R¹ is selected from unsubstituted pyridinyl, pyridinyl substituted    by (C₁-C₄)-alkyl, and the corresponding pyridine-N-oxide of    pyridinyl substituted by (C₁-C₄)-alkyl,-   R² is selected from hydrogen, halogen and (C₁-C₄)-alkyl, and-   R³ is selected from hydrogen, halogen and (C₁-C₄)-alkyl.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by    fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is hydrogen,-   R¹ is selected from unsubstituted pyridinyl, pyridinyl substituted    by (C₁-C₄)-alkyl, and the corresponding pyridine-N-oxide of    pyridinyl substituted by (C₁-C₄)-alkyl, and-   R² and R³ are hydrogen.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    (C₁-C₄)-alkyl substituted by fluorine, and unsubstituted    (C₁-C₄)-alkoxy,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is hydrogen,-   R¹ is unsubstituted pyridin-4-yl or pyridin-4-yl substituted by    (C₁-C₄)-alkyl, and-   R² and R³ are hydrogen.

In still another embodiment, the present invention provides a compoundof formula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is (C₁-C₄)-alkyl substituted by fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)—, alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen,-   L is ═N—,-   M is ═C(R⁷)—, wherein R⁷ is hydrogen,-   R¹ is unsubstituted pyridin-4-yl or pyridin-4-yl substituted by    (C₁-C₄)-alkyl, and-   R² and R³ are hydrogen.

In another embodiment, the present invention provides a compound offormula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by    fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═C(H)—,-   M is ═N—,-   R¹ is selected from —CN, unsubstituted pyridinyl, pyridinyl    substituted by (C₁-C₄)-alkyl, and the corresponding pyridine-N-oxide    of pyridinyl substituted by (C₁-C₄)-alkyl,-   R² is selected from hydrogen, halogen and (C₁-C₄)-alkyl, and-   R³ is selected from hydrogen, halogen and (C₁-C₄)-alkyl.

In another embodiment, the present invention provides a compound offormula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by    fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by    fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═C(H)—,-   M is ═N—,-   R¹ is —CN,-   R² is selected from hydrogen, halogen and (C₁-C₄)-alkyl, and-   R³ is selected from hydrogen, halogen and (C₁-C₄)-alkyl.

In another embodiment, the present invention provides a compound offormula I wherein

-   A is ═C(R⁴)—, wherein R⁴ is hydrogen or halogen,-   D is ═C(R⁵)—, wherein R⁵ is hydrogen,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen,-   L is ═C(H)—,-   M is ═N—,-   R¹ is —CN, and-   R² and R³ are hydrogen.

In one embodiment, the present invention provides a compound of formulaI selected from

-   2-phenyl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile,-   2-(3-chloro-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile,-   2-(4-trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile,-   5-(4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile,-   5-(4-fluoro-3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile,-   5-(3-chloro-4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile,-   5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile,-   5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile,-   5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile,    and-   5-(3,4-dichloro-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile.

In another embodiment, the present invention provides a compound offormula I selected from

-   5-(4-chloro-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-chloro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-chloro-3-methyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-chloro-4-fluoro-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-chloro-4-fluoro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3,4-dichloro-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3,4-dichloro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile,-   5-(4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,    and-   5-(3-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine.

In one embodiment, the present invention provides a compound of formulaI selected from

-   5-(3-fluoro-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-chloro-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-chloro-3-methyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-chloro-4-fluoro-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3,4-dichloro-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-fluoro-4-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-methyl-3-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,    and-   5-(4-chloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine.

In another embodiment, the present invention provides a compound offormula I selected from

-   5-(4-chloro-3-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-chloro-4-fluoro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3,4-dichloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-fluoro-4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   2-(4-methyl-3-trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile,-   5-(3-methyl-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-methyl-4-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,    and-   5-(3-methyl-4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine.

In another embodiment, the present invention provides a compound offormula I selected from

-   2-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-8-carbonitrile,-   2-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile,-   2-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-8-carbonitrile,-   2-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile,-   5-(4-ethoxy-3-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-trifluorothoxy-3-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-ethoxy-3-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-methyl-4-trifluoromethyl-phenyl)-3-(2-hydroxymethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,    and-   5-(4-chloro-3-methyl-phenyl)-3-(2-methyl-1-oxy-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine.

In another embodiment, the present invention provides a compound offormula I selected from

-   2-(4-Chloro-3-methyl-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(3-Chloro-4-fluoro-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(4-Dichloro-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   8-Pyridin-3-yl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine,-   2-(3-Methyl-4-trifluoromethyl-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(4-Chloro-3-methyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(3-Chloro-4-fluoro-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(4-Dichloro-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   8-Pyridin-4-yl-4-trifluoromethyl-2-(3-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine,    and-   8-Pyridin-4-yl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine.

In another embodiment, the present invention provides a compound offormula I selected from

-   2-(4-Methyl-3-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(4-Ethoxy-3-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   8-Pyridin-4-yl-2-[4-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-phenyl]-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(3-Methyl-4-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(4-Chloro-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(3-Chloro-4-fluoro-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(4-Dichloro-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   8-(2-Methyl-pyridin-4-yl)-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine,-   2-(4-Ethoxy-3-trifluoromethyl-phenyl)-8-(2-methyl-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,    and-   8-(2-Methyl-pyridin-4-yl-2-[4-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-phenyl]-4-trifluoromethyl-imidazo[1,5-a]pyrimidine.

In another embodiment, the present invention provides a compound offormula I selected from

-   2-(3-Methyl-4-trifluoromethyl-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   {4-[5-(4-Chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-yl}-methanol,-   {4-[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-yl}-methanol,-   5-(3-Ethoxy-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-Ethoxy-4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   2-(3-Ethoxy-4-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   3-Pyridin-4-yl-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   3-(2,6-Dimethyl-pyridin-4-yl)-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   3-(2-Methyl-pyridin-4-yl)-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,    and-   8-Pyridin-4-yl-2-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4-trifluoromethyl-imidazo[1,5-a]pyrimidine.

In another embodiment, the present invention provides a compound offormula I selected from

-   8-(2-Methyl-pyridin-4-yl)-2-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   5-(3,4-Bis-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3,4-Bis-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   2-(3,4-Bis-trifluoromethyl-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   2-(4-Bromo-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine,-   5-(4-Bromo-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-Bromo-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   7-Difluoromethyl-3-pyridin-4-yl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine,-   7-Difluoromethyl-3-(2-methyl-pyridin-4-yl)-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine,    and-   7-Difluoromethyl-3-(2-methyl-pyridin-4-yl)-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine.

In another embodiment, the present invention provides a compound offormula I selected from

-   5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile,-   5-(4-chloro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-chloro-3-methyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-chloro-4-fluoro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-fluoro-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-chloro-3-methyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3,4-dichloro-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,    and-   5-(3-fluoro-4-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine.

In another embodiment, the present invention provides a compound offormula I selected from

-   5-(4-chloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3,4-dichloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-methyl-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-methyl-4-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,-   5-(3-methyl-4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine,    and-   5-(4-ethoxy-3-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine.

The present invention also provides a process for the preparation of acompound of formula I comprising reacting a compound of formula II

wherein

-   A is ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxy substituted by    fluorine, unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl    substituted by fluorine,-   D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,    unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,    unsubstituted (C₃-C₆)-cycloalkyl and (C₃- C₆)-cycloalkyl substituted    by fluorine,-   E is ═C(R⁶)—, wherein R⁶ is hydrogen or halogen, or one of A, D and    E is ═N—,-   R² is selected from hydrogen, halogen, (C₁-C₄)-alkyl and    (C₃-C₆)-cycloalkyl, and-   R³ is selected from hydrogen, halogen, (C₁-C₄)-alkyl and    (C₃-C₆)-cycloalkyl,-   with a compound of formula III

wherein

-   L is ═N— or ═C(H)—,-   M is ═C(R⁷)—, when L is ═N—, or M is ═N—, when L is ═C(H)—,-   R¹ is selected from —CN, unsubstituted pyridinyl, pyridinyl    substituted by (C₁- C₄)-alkyl and the corresponding pyridine-N-oxide    of pyridinyl substituted by (C₁-C₄)-alkyl, and-   R⁷ is selected from hydrogen, unsubstituted (C₁-C₄)-alkyl,    (C₁-C₄)-alkyl substituted by CN, unsubstituted (C₃-C₆)-cycloalkyl    and (C₃-C₆)-cycloalkyl substituted by CN.

The starting compounds of formula II and III are known or may beprepared from corresponding known compounds.

The reaction may take place in the presence of a solvent, e.g. aceticacid, under, e.g., reflux conditions. The preparation of compounds offormula I is illustrated in the following examples.

EXAMPLE S1 Preparation of 1-phenyl-4,4,4-trifluoro-butane-1,3-diones

(General Procedure A)

To a stirred solution of ethyl trifluoroacetate (1.1 eq.) intert-butyl-methyl-ether was added dropwise a 5.4M solution of sodiummethanolate in methanol followed by a solution of an acetophenonederivative (1.1 eq.) in tert-butyl-methyl-ether. The reaction mixturewas stirred at room temperature for 20 h, poured into ice/water,acidified with 2N HCl and extracted with diethyl ether (two times). Thecombined organic layers were washed with brine (two times), dried(MgSO₄) and evaporated. The product was used without furtherpurification.

acetophenone derivative resulting1-phenyl-4,4,4-trifluoro-butane-1,3-dione No. 3-chloro-acetophenone1-(3-chloro-phenyl)-4,4,4-trifluoro-butane-1,3- S1.1 dione4-methyl-acetophenone 1-(4-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-S1.2 dione 2-chloro-acetophenone1-(2-chloro-phenyl)-4,4,4-trifluoro-butane-1,3- S1.3 dione 2,4-dichloro-1-(2,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione S1.4acetophenone 3-methyl-acetophenone1-(3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione S1.53-trifluoromethyl- 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro- S1.6acetophenone butane-1,3-dione 4-trifluoromethyl-1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro- S1.7 acetophenonebutane-1,3-dione 3-fluoro-acetophenone1-(3-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3- S1.8 dione4-fluoro-acetophenone 1-(4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-S1.9 dione 2,4-difluoro-1-(2,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3- S1.10 acetophenonedione 2-fluoro-acetophenone1-(2-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3- S1.11 dione3,4-difluoro- 1-(3,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3- S1.12acetophenone dione 4-fluoro-3-1-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,4- S1.13 trifluoromethyl-trifluoro-butane-1,3-dione acetophenone 3-chloro-4-fluoro-1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro- S1.14 acetophenonebutane-1,3-dione 4-chloro-3-methyl-1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro- S1.15 acetophenonebutane-1,3-dione 3,4-dichloro-1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3- S1.16 acetophenonedione 4-chloro-acetophenone1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3- S1.17 dione 3-fluoro-4-1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4- S1.18 trifluoromethyl-trifluoro-butane-1,3-dione acetophenone 3-methyl-4-1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4- S1.19 trifluoromethyl-trifluoro-butane-1,3-dione acetophenone 4-trifluoroethoxy-3-1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)- S1.20 trifluoromethyl-4,4,4-trifluoro-butane-1,3-dione acetophenone 4-methyl-3-1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4- S1.21 trifluoromethyl-trifluoro-butane-1,3-dione acetophenone 4-ethoxy-3-1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4- S1.22 trifluoromethyl-trifluoro-butane-1,3-dione acetophenone acetophenone1-phenyl-4,4,4-trifluoro-butane-1,3-dione S1.23 4-methoxy-1-(4-methoxy-phenyl)-4,4,4-trifluoro-butane-1,3- S1.24 acetophenonedione 2-methyl-acetophenone1-(2-methyl-phenyl)-4,4,4-trifluoro-butane-1,3- S1.25 dione 3-ethoxy-4-1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4- S1.26 trifluoromethyl-trifluoro-butane-1,3-dione acetophenone 3-(2,2,2-1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl- S1.27trifluoroethoxy)-4- phenyl]-4,4,4-trifluoro-butane-1,3-dionetrifluoromethyl- acetophenone 3,4-bis-trifluoromethyl-1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro- S1.28 acetophenonebutane-1,3-dione 4-bromo-acetophenone1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3- S1.29 dione 4-methoxy-4,4-difluoro-1-(4-methoxy-phenyl)-butane-1,3- S1.30 acetophenone dioneNo.: compound number of resulting1-phenyl-4,4,4-trifluoro-butane-1,3-dione

EXAMPLE S2 Preparation of 1-pyridinyl-4,4,4-trifluoro-butane-1,3-diones

(General Procedure A)

To a stirred solution of ethyl trifluoroacetate (1.1 eq.) intert-butyl-methyl-ether was added dropwise a 5.4M solution of sodiummethanolate in methanol followed by a solution of an acetylpyridinederivative (1.1 eq.) in tert-butyl-methyl-ether. The reaction mixturewas stirred at room temperature for 20 h, poured into ice/water,acidified with 2N HCl and extracted with diethyl ether (two times). Thecombined organic layers were washed with water (20 ml), the combinedwater layers neutralized with sat. NaHCO₃ solution and evaporated todryness. The obtained solid was stirred three times in warmdichloromethane/MeOH 9:1 and filtered. The combined organic layers weredried (MgSO₄) and evaporated. The crude product can be further purifiedby crystallization.

acetylpyridine resulting derivative1-phenyl-4,4,4-trifluoro-butane-1,3-dione No. 2-acetylpyridine1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione S2.1 3-acetylpyridine1-pyridin-3-yl-4,4,4-trifluoro-butane-1,3-dione S2.2 4-acetylpyridine1-pyridin-4-yl-4,4,4-trifluoro-butane-1,3-dione S2.3

EXAMPLE S3 Preparation of 3-amino-pyridinyl-pyrazoles

Following a procedure as described in Bioorg. Med. Chem. Lett. 12 (2002)3537-3541] the following 3-amino-pyridinyl-pyrazoles were preparedstarting from the appropriate pyridine:

pyridine resulting 3-amino-pyridinyl-pyrazole [CAS No.] No.3-cyanomethyl-pyridine 3-amino-4-(3-pyridinyl)-pyrazole [40545-68-2]S3.1 4-cyanomethyl-pyridine 3-amino-4-(4-pyridinyl)-pyrazole[216661-87-9] S3.2 2-cyanomethyl-pyridine3-amino-4-(2-pyridinyl)-pyrazole [493038-87-2] S3.34-cyanomethyl-2,6-dimethyl-3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole S3.4 pyridine[130138-46-4] 4-cyanomethyl-2-methyl-3-amino-4-(2-methyl-4-pyridinyl)-pyrazole S3.5 pyridine [130138-46-4]No.: compound number of resulting 3-amino-pyridinyl-pyrazole

EXAMPLE S4 Preparation of 4-(2-Methyl-pyridin-4-yl)-2H-pyrazol-3-ylamine

To a stirred mixture of 4-hydroxymethyl-2-methyl-pyridine [CAS No.105250-16-6] (3.37 g, 27.4 mmol), potassium cyanide (3.56 g, 54.7 mmol)and 18-crown-6 (0.72 g, 2.74 mmol) in acetonitrile (75 ml) was addeddropwise at 15-20° C. a solution of tributylphosphine (7.16 g, 30.1mmol) in acetonitrile (25 ml). The reaction mixture was stirred at roomtemperature for 25 h, poured into water (100 ml) and extracted withethyl acetate (3×100 ml). The combined organic layers were washed withwater (3×100 ml), brine (100 ml) dried (MgSO₄) and evaporated. The crudeproduct was further purified by column chromatography on silica gel(ethyl acetate) to yield 4-cyanomethyl-2-methyl-pyridine (2.26 g, 62%)as a brown oil.

A stirred mixture of 4-cyanomethyl-2-methyl-pyridine (2.51 g, 19.0 mmol)and N,N-dimethylformamide-dimethylacetal (7.63 ml, 57.0 mmol) was heatedunder reflux conditions for 15 min, evaporated and the crude productpurified by column chromatography on silica gel(dichloromethane/methanol/NH4OH 80:10:1) to give 2.08 g of a solid,which was crystallized from diethyl ether/hexane to yield3-dimethylamino-2-(2-methyl-pyridin-4-yl)-acrylonitrile (1.94 g, 55%) asa brown solid; mp 126° C.

c) To stirred solution of3-dimethylamino-2-(2-methyl-pyridin-4-yl)-acrylonitrile (1.8 g, 9.61mmol) in ethanol (18 ml) was added at room temperature hydrazinemonohydrate (1.03 ml, 21.1 mmol), the reaction mixture was heated underreflux conditions for 16 h and evaporated. Purification by columnchromatography on silica gel (dichloromethane/methanol/NH4OH 80:10:1)and crystallization from diethyl ether yielded4-(2-methyl-pyridin-4-yl)-2H-pyrazol-3-ylamine (0.6 g, 36%) as an orangesolid.

MS (ISP) 175.1 [(M+H)⁺]; mp 230° C.

EXAMPLE S5 Preparation of4-(2,6-Dimethyl-pyridin-4-yl)-2H-pyrazol-3-ylamine

A stirred mixture of 4-cyanomethyl-2,6-dimethyl-pyridine [CAS No.130138-46-4] (2.20 g, 15.1 mmol) andN,N-dimethylformamide-dimethylacetal (6.04 ml, 45.2 mmol) was heatedunder reflux conditions for 15 min, evaporated and the crude productpurified by column chromatography on silica gel(dichloromethane/methanol/NH₄OH 80:10:1) to give 2.6 g of a solid, whichwas crystallized from diethyl ether/hexane to yield3-dimethylamino-2-(2,6-dimethyl-pyridin-4-yl)-acrylonitrile (2.44 g,81%) as a brown solid; mp 149° C.

b) To stirred solution of3-dimethylamino-2-(2,6-dimethyl-pyridin-4-yl)-acrylonitrile (2.2 g, 10.9mmol) in ethanol (22 ml) was added at room temperature hydrazinemonohydrate (1.17 ml, 24.1 mmol), the reaction mixture was heated underreflux conditions for 23 h and evaporated. Purification by columnchromatography on silica gel (dichloromethane/methanol/NH₄OH 80:10:1)and crystallization from diethyl ether yielded4-(2,6-dimethyl-pyridin-4-yl)-2H-pyrazol-3-ylamine (0.8 g, 39%) as alight brown solid. MS (ISP) 189.3 [(M+H)⁺]; mp 222° C.

EXAMPLE S6 2-Amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride

To a stirred solution of sulfuric acid (14 ml, 95-97%) and HNO₃ (10 ml,fum.) was added at 0° C. 3-(3-pyridinyl)-1H-imidazole [CAS No.51746-85-1, commercially available] (4.25 g, 29.3 mmol). The reactionmixture was stirred at room temperature for 45 min and at 50° C. for 6 hand poured into ice-water (100 ml). Solid NaHCO₃ was added to thestirred mixture until the pH reached 5-6, the precipitated product wascollected by filtration and washed with water and hexane to yield2-nitro-3-(3-pyridinyl)-1H-imidazole (5.53 g, 99%) as an off-whitesolid; mp 261° C.

b) A stirred solution of 2-nitro-3-(3-pyridinyl)-1H-imidazole (5.14 g,27.0 mmol) in methanol (800 ml) was hydrogenated at room temperature onRaney Nickel (2.5 g) for 4 h. The catalyst was removed by filtration, 3Nhydrochloric acid (30 ml) was added and the solution evaporated to 50ml. While stirring diethyl ether was added and the precipitated productwas collected by filtration to yield2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride (5.39 g, 86%) as abrown solid. MS (ISP) 161.2 [(M+H)⁺]; mp 253° C.

EXAMPLE S7 2-Amino-3-(4-pyridinyl)-1H-imidazole

To a stirred solution of sulfuric acid (21 ml, 95-97%) and HNO₃ (15 ml,fum.) was added at 0° C. 3-(4-pyridinyl)-1H-imidazole [CAS No.51746-87-3] (6.36 g, 43.8 mmol). The reaction mixture was stirred atroom temperature for 45 min, at 55° C. for 23 h and at 100° C. for 2 hand poured into ice-water (200 ml). Sodium hydroxide solution (32%) wasadded to the stirred mixture until the pH reached 5-6, the precipitatedproduct was collected by filtration and washed with water and hexane toyield 2-nitro-3-(4-pyridinyl)-1H-imidazole (7.95 g, 95%) as a lightyellow solid; mp 234° C.

b) A stirred solution of 2-nitro-3-(4-pyridinyl)-1H-imidazole (1.19 g,6.26 mmol) in 7N methanol/NH₃ (25 ml) and methanol (25 ml) washydrogenated at room temperature on Raney Nickel (1 g) for 4 h. Thecatalyst was removed by filtration and the solution evaporated. Thecrude product was purified by column chromatography on silica gel(dichloromethane/methanol/NH₄OH 40:10:1) to yield2-amino-3-(4-pyridinyl)-1H-imidazole (0.85 g, 85%) as a green solid. MS(ISP) 161.2 [(M+H)⁺]; mp 190° C.

EXAMPLE S8 2-Amino-3-(2-methyl-4-pyridinyl)-1H-imidazole

To a stirred suspension of 4-acetyl-2-methyl-pyridine [CAS No.2732-28-7] (9.7 g, 71.8 mmol) in water (115 ml) was added at roomtemperature hydroxylamine hydrochloride (8.48 g, 122 mmol) and themixture was heated to 70° C. At this temperature methanol (145 ml) wasadded dropwise over a period of 15 min and afterwards a solution ofsodium acetate trihydrate (25.4 g, 187 mmol) in water (115 ml) was addeddropwise over a period of 15 min. The reaction mixture was stirred at80° C. for 3.5 h, brine (150 ml) was added and the solution wasextracted with ethyl acetate (2×250 ml). The combined organic layerswere washed with brine (150 ml), dried (MgSO₄) and evaporated. The crudeproduct was purified by crystallization from ethyl acetate/hexane togive 1-(2-methyl-pyridin-4-yl)-ethanone oxime (7.25 g, 67%) as anoff-white solid; mp 154° C.

b) To a stirred solution of 1-(2-methyl-pyridin-4-yl)-ethanone oxime(7.14 g, 47.5 mmol) in pyridine (20 ml) was added at room temperaturetoluene-4-sulfonyl chloride (9.88 g, 51.8 mmol), the reaction mixturewas stirred for 3 h, poured into ice-water (300 ml) and the precipitatedsolid collected by filtration. Hexane (100 ml) was added, the mixturewas stirred at room temperature for 1 h and the product collected byfiltration to give1-(2-methyl-pyridin-4-yl)-(O-toluene-4-sulfonyl)-ethanone oxime (11.1 g,77%) as a white solid; mp 91° C.

c) To a stirred suspension of1-(2-methyl-pyridin-4-yl)-(O-toluene-4-sulfonyl)-ethanone oxime (11.0 g,36.1 mmol) in ethanol (35 ml) was added a solution of potassiumethanolate (5.03 g, 56.7 mmol) in ethanol (35 ml) and the reactionmixture was stirred at room temperature for 17 h. The precipitated solidwas collected by filtration and washed with diethyl ether (200 ml). Thecombined filtrates were washed with 2N HCl (2×80 ml, 1×40 ml) and thecombined water layers evaporated to give crude1-(2-methyl-pyridin-4-yl)-2-amino-ethanone dihydrochloride (8.51 g, 99%)as a light brown solid, which was used without further purification.

d) To a stirred solution of crude1-(2-methyl-pyridin-4-yl)-2-amino-ethanone dihydrochloride (8.50 g, 35.8mmol) in water (60 ml) was added at room temperature potassiumthiocyanate (16.4 g, 168 mmol) and the reaction mixture was heated underreflux conditions for 3 h and at 0° C. for 2 h. The precipitated solidwas collected by filtration, saturated sodium bicarbonate solution (100ml) was added and the mixture was stirred at room temperature for 2 h.The product was collected by filtration to give4-(2-methyl-pyridin-4-yl)-1,3-dihydro-imidazole-2-thione (5.44 g, 79%)as a light brown solid; MS (ISP) 192.2 [(M+H)⁺].

e) To a stirred solution of HNO₃ (43.3 ml, 65%) and water (130 ml) wasadded at 80° C. in small portions4-(2-methyl-pyridin-4-yl)-1,3-dihydro-imidazole-2-thione (5.20 g, 27.2mmol) and the mixture was heated under reflux conditions for 2 h. Thereaction mixture was cooled (ice) and solid NaHCO₃ was added to get abasic solution. Solid NaCl was added and the solution was extracted withTHF (3×200 ml). The combined organic layers were dried (MgSO₄) andevaporated to give 3-(2-methyl-4-pyridinyl)-1H-imidazole (4.16 g, 96%)as a yellow solid; MS (ISP) 160.2 [(M+H)⁺].

f) To a stirred solution of sulfuric acid (14 ml, 95-97%) and HNO₃ (10ml, fum.) was added at 0° C. 3-(2-methyl-4-pyridinyl)-1H-imidazole (4.0g, 25.1 mmol). The reaction mixture was stirred at room temperature for50 min, at 100° C. for 2.5 h and at 110° C. for 10 h and poured intoice-water (70 ml). Solid NaHCO₃ was added to the stirred mixture untilthe pH reached 5. The solution was extracted with THF (4×200 ml), thecombined organic layers were dried (MgSO4) and evaporated to give2-nitro-3-(2-methyl-4-pyridinyl)-1H-imidazole (3.4 g, 66%) as a lightyellow solid; MS (ISP) 205.2 [(M+H)⁺].

g) A stirred solution of 2-nitro-3-(2-methyl-4-pyridinyl)-1H-imidazole(3.40 g, 16.6 mmol) in 7N methanol/NH₃ (70 ml) and methanol (70 ml) washydrogenated at room temperature on Raney Nickel (2.9 g) for 2 h. Thecatalyst was removed by filtration and the solution evaporated. Thecrude product was purified by column chromatography on silica gel(dichloromethane/methanol/NH₄OH 40:10:1) to yield2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole (1.71 g, 59%) as a greensolid. MS (ISP) 175.1 [(M+H)⁺]; mp 167° C.

EXAMPLE 1 Preparation ofphenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitriles andpyridinyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitriles

(General Procedure B)

A stirred mixture of commercially available 3-amino-4-cyano-pyrazole (1eq.) and a 1-phenyl-4,4,4-trifluoro-butane-1,3-dione or1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione (1 eq.), preparedaccording to general procedure A, in acetic acid was heated under refluxconditions for 3.5 h. The reaction mixture was evaporated and theproduct was isolated by column chromatography (heptane/ethyl acetate)and further purified by crystallization. If the product precipitatesduring the reaction it can be isolated by filtration and furtherpurified by crystallization.

Ex. dione compound name MS (ISP)/mp 1.1 S1.15-(3-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5- 323.1 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 204° C. 1.2 S1.25-(4-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5- 303.1 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 121° C. 1.3 S1.35-(2-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5- 323.1 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 169° C. 1.4 S1.45-(2,4-dichloro-phenyl)-7-trifluoromethyl- 357.1 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 180° C. 1.5 S1.55-(3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5- 303.2 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 202° C. 1.6 S1.65-(3-trifluoromethyl-phenyl)-7-trifluoromethyl- 357.0 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 192° C. 1.7 S1.75-(4-trifluoromethyl-phenyl)-7-trifluoromethyl- 357.0 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 176° C. 1.8 S1.85-(3-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5- 306.9 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 199° C. 1.9 S1.95-(4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5- 306.9 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 198° C. 1.10 S1.105-(2,4-difluoro-phenyl)-7-trifluoromethyl- 325.0 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 149° C. 1.11 S1.115-(2-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5- 307.1 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 165° C. 1.12 S1.125-(3,4-difluoro-phenyl)-7-trifluoromethyl- 325.0 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 192° C. 1.13 S1.135-(4-fluoro-3-trifluoromethyl-phenyl)-7- 375.0 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3- mp 204° C. carbonitrile1.14 S1.14 5-(3-chloro-4-fluoro-phenyl)-7-trifluoromethyl- 341.0 [(M +H)⁺] pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 190° C. 1.15 S1.155-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl- 337.1 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 216° C. 1.16 S1.165-(3,4-dichloro-phenyl)-7-trifluoromethyl- 356.9 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 206° C. 1.17 S1.185-(3-fluoro-4-trifluoromethyl-phenyl)-7- 375.0 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3- mp 184° C. carbonitrile1.18 S1.19 2-(3-methyl-4-trifluoromethyl-phenyl)-4- 371.1 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine-8-carbonitrile mp 209° C. 1.19S1.20 2-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4- 453.0 [M⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine-8- mp 215° C. carbonitrile1.20 S2.1 5-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5- 289.9 [(M +H)⁺] a]pyrimidine-3-carbonitrile mp 208° C. 1.21 S2.25-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5- 290.2 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 193° C. 1.22 S2.35-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5- 289.8 [(M + H)⁺]a]pyrimidine-3-carbonitrile mp 233° C.

EXAMPLE 1.15-(3-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(3-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251mg, 1.0 mmol), prepared from commercially available3-chloro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (150 mg, 46%).MS (ISP) 323.1 [(M+H)⁺]; mp 204° C.

EXAMPLE 1.25-(4-Methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(4-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230mg, 1.0 mmol), prepared from commercially available4-methyl-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a light yellow solid (151 mg,50%). MS (ISP) 303.1 [(M+H)⁺]; mp 121° C.

EXAMPLE 1.35-(2-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(2-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251mg, 1.0 mmol), prepared from commercially available2-chloro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as an off-white solid (73 mg,23%). MS (ISP) 323.1 [(M+H)⁺]; mp 169° C.

EXAMPLE 1.45-(2,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(2,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(285 mg, 1.0 mmol), prepared from commercially available2,4-dichloro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a light brown solid (63 mg,18%). MS (ISP) 357.1 [(M+H)⁺]; mp 180° C.

EXAMPLE 1.55-(3-Methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230mg, 1.0 mmol), prepared from commercially available3-methyl-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (164 mg, 54%).MS (ISP) 303.2 [(M+H)⁺]; mp 202° C.

EXAMPLE 1.65-(3-Trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg,1.0 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a white solid (151 mg, 42%).MS (ISP) 357.0 [(M+H)⁺]; mp 192° C.

EXAMPLE 1.75-(4-Trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg,1.0 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as an off-white solid (137 mg,38%). MS (ISP) 357.0 [(M+H)⁺]; mp 176° C.

EXAMPLE 1.85-(3-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(3-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234mg, 1.0 mmol), prepared from commercially available3-fluoro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a light yellow solid (141 mg,46%). MS (ISP) 306.9 [(M+H)⁺]; mp 199° C.

EXAMPLE 1.95-(4-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234mg, 1.0 mmol), prepared from commercially available4-fluoro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (118 mg, 39%).MS (ISP) 306.9 [(M+H)⁺]; mp 198° C.

EXAMPLE 1.105-(2,4-Difluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(2,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(252 mg, 1.0 mmol), prepared from commercially available2,4-difluoro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a light yellow solid (72 mg,22%). MS (ISP) 325.0 [(M+H)⁺]; mp 149° C.

EXAMPLE 1.115-(2-Fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(2-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234mg, 1.0 mmol), prepared from commercially available2-fluoro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a light yellow solid (83 mg,27%). MS (ISP) 307.1 [(M+H)⁺]; mp 165° C.

EXAMPLE 1.125-(3,4-Difluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(3,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(252 mg, 1.0 mmol), prepared from commercially available3,4-difluoro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a light yellow solid (137 mg,42%).

EXAMPLE 1.135-(4-Fluoro-3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(302 mg, 1.0 mmol), prepared from commercially available4-fluoro3-trifluoromethyl-acetophenone according to general procedure A,and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as an off-white solid (144 mg,38%). MS (ISP) 375.0 [(M+H)⁺]; mp 204° C.

EXAMPLE 1.145-(3-Chloro-4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg,1.0 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as an off-white solid (109 mg,32%). MS (ISP) 341.0 [(M+H)⁺]; mp 190° C.

EXAMPLE 1.155-(4-Chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (264 mg,1.0 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as an off-white solid (128 mg,38%). MS (ISP) 337.1 [(M+H)⁺]; mp 216° C.

EXAMPLE 1.165-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(285 mg, 1.0 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (140 mg, 39%).MS (ISP) 356.9 [(M+H)⁺]; mp 206° C.

EXAMPLE 1.175-(3-Fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(302 mg, 1.0 mmol), prepared from commercially available3-fluoro-4-trifluoromethyl-acetophenone according to general procedureA, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as an off-white solid (139 mg,37%). MS (ISP) 375.0 [(M+H)⁺]; mp 184° C.

EXAMPLE 1.182-(3-Methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(224 mg, 0.75 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-cyano-pyrazole (81 mg, 0.75 mmol) according to generalprocedure B yielded the title compound as an off-white solid (142 mg,51%). MS (ISP) 371.1 [(M+H)⁺]; mp 209° C.

EXAMPLE 1.192-(4-Trifluoroethoxy-3-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(382 mg, 1.0 mmol), prepared from4-trifluoroethoxy-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as an off-white solid (226 mg,50%). MS (ISP) 453.0 [M⁺]; mp 215° C.

EXAMPLE 1.205-Pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0mmol), prepared from commercially available 2-acetylpyridine accordingto general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol)according to general procedure B yielded the title compound as a lightbrown solid (135 mg, 47%). MS (ISP) 289.9 [(M+H)⁺]; mp 208° C.

EXAMPLE 1.215-Pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-pyridin-3-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0mmol), prepared from commercially available 3-acetylpyridine accordingto general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol)according to general procedure B yielded the title compound as anoff-white solid (45 mg, 16%). MS (ISP) 290.2 [(M+H)⁺]; mp 193° C.

EXAMPLE 1.225-Pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-pyridin-4-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0mmol), prepared from commercially available 4-acetylpyridine accordingto general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol)according to general procedure B yielded the title compound as a lightyellow solid (110 mg, 38%). MS (ISP) 289.8 [(M+H)⁺]; mp 233° C.

EXAMPLE 2 Preparation ofphenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitriles

(General Procedure B)

A stirred mixture of commercially available3-amino-4-cyano-5-methyl-pyrazole (1 eq.) and a1-phenyl-4,4,4-trifluoro-butane-1,3-dione (1 eq.), prepared according togeneral procedure A, in acetic acid was heated under reflux conditionsfor about 3.5 h. The reaction mixture was evaporated and the product wasisolated by column chromatography (heptane/ethyl acetate) and furtherpurified by crystallization. If the product precipitates during thereaction it can be isolated by filtration and further purified bycrystallization.

Ex. dione compound name MS (ISP)/mp 2.1 S1.72-methyl-5-(4-trifluoromethyl-phenyl)-7- 371.1 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3- mp 184° C. carbonitrile 2.2S1.6 2-methyl-5-(3-trifluoromethyl-phenyl)-7- 371.1 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3- mp 215° C. carbonitrile 2.3S1.17 5-(4-chloro-phenyl)-2-methyl-7-trifluoromethyl- 337.1 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 238° C. 2.4 S1.145-(3-chloro-4-fluoro-phenyl)-2-methyl-7- 355.0 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile mp 196° C.

EXAMPLE 2.12-Methyl-5-(4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg,1.0 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, andcommercially available 3-amino-4-cyano-5-methyl -pyrazole (122 mg, 1.0mmol) according to general procedure B yielded the title compound as alight yellow solid (234 mg, 63%). MS (ISP) 371.1 [(M+H)⁺]; mp 184° C.

EXAMPLE 2.22-Methyl-5-(3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg,1.0 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, andcommercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0mmol) according to general procedure B yielded the title compound as alight yellow solid (272 mg, 73%). MS (ISP) 371.1 [(M+H)⁺]; mp 215° C.

EXAMPLE 2.35-(4-Chloro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251mg, 1.0 mol), prepared from commercially available 4-chloro-acetophenoneaccording to general procedure A, and commercially available3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according togeneral procedure B yielded the title compound as a yellow solid (222mg, 66%). MS (ISP) 337.1 [(M+H)⁺]; mp 238° C.

EXAMPLE 2.45-(3-Chloro-4-fluoro-phenyl)-2-methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg,1.0 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, andcommercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0mmol) according to general procedure B yielded the title compound as alight yellow solid (243 mg, 69%). MS (ISP) 355.0 [(M+H)⁺]; mp 196° C.

EXAMPLE 3 Preparation ofphenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitriles

(General Procedure B)

A stirred mixture of commercially available3-amino-4-cyano-5-cyanomethyl-pyrazole (1 eq.) and a1-phenyl-4,4,4-trifluoro-butane-1,3-dione (1 eq.), prepared according togeneral procedure A, in acetic acid was heated under reflux conditionsfor 3.5 h. The reaction mixture was evaporated and the product wasisolated by column chromatography (heptane/ethyl acetate) and furtherpurified by crystallization. If the product precipitates during thereaction it can be isolated by filtration and further purified bycrystallization.

Ex. dione compound name MS (ISP)/mp 3.1 S1.145-(3-chloro-4-fluoro-phenyl)-2-cyanomethyl-7- 380.1trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3- [(M + H)⁺] carbonitrile mp185° C. 3.2 S1.15 5-(4-chloro-3-methyl-phenyl)-2-cyanomethyl-7- 376.1trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3- [(M + H)⁺] carbonitrile mp238° C.

EXAMPLE 3.15-(3-Chloro-4-fluoro-phenyl)-2-cyanomethyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg,1.0 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, andcommercially available 3-amino-4-cyano-5-cyanomethyl-pyrazole (147 mg,1.0 mmol) according to general procedure B yielded the title compound asa light yellow solid (223 mg, 59%). MS (ISP) 380.1 [(M+H)⁺]; mp 185° C.

EXAMPLE 3.25-(4-Chloro-3-methyl-phenyl)-2-cyanomethyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg,0.5 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, andcommercially available 3-amino-4-cyano-5-cyanomethyl-pyrazole (74 mg,0.5 mmol) according to general procedure B yielded the title compound asa light yellow solid (99 mg, 53%). MS (ISP) 376.1 [(M+H)⁺]; mp 238° C.

EXAMPLE 4 Preparation of5-phenyl-3-pyridinyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidines

(General Procedure B)

A stirred mixture of a 3-amino-4-pyridinyl-pyrazole (1 eq.) and a1-phenyl-4,4,4-trifluoro-butane-1,3-dione (1 eq.), prepared according togeneral procedure A, in acetic acid was heated under reflux conditionsfor 3.5 h. The reaction mixture was evaporated and the product wasisolated by column chromatography (heptane/ethyl acetate) and furtherpurified by crystallization. If the product precipitates during thereaction it can be isolated by filtration and further purified bycrystallization.

Ex. dione pyrazole compound name MS (ISP)/mp 4.1 S1.17 S3.15-(4-chloro-phenyl)-3-pyridin-3-yl-7- 375.3 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine mp 188° C. 4.2 S1.17 S3.25-(4-chloro-phenyl)-3-pyridin-4-yl-7- 375.3 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine mp 274° C. 4.3 S1.15 S3.15-(4-chloro-3-methyl-phenyl)-3-pyridin-3- 375.3 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 193° C. a]pyrimidine 4.4 S1.15S3.2 5-(4-chloro-3-methyl-phenyl)-3-pyridin-4- 389.2 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 247° C. a]pyrimidine 4.5 S1.15S3.3 5-(4-chloro-3-methyl-phenyl)-3-pyridin-2- 389.2 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 183° C. a]pyrimidine 4.6 S1.14S3.1 5-(3-chloro-4-fluoro-phenyl)-3-pyridin-3- 393.1 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 190° C. a]pyrimidine 4.7 S1.14S3.2 5-(3-chloro-4-fluoro-phenyl)-3-pyridin-4- 393.1 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 265° C. a]pyrimidine 4.8 S1.14S3.3 5-(3-chloro-4-fluoro-phenyl)-3-pyridin-2- 393.1 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 197° C. a]pyrimidine 4.9 S1.16S3.1 5-(3,4-dichloro-phenyl)-3-pyridin-3-yl-7- 409.1 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine mp 224° C. 4.10 S1.16 S3.25-(3,4-dichloro-phenyl)-3-pyridin-4-yl-7- 409.2 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine mp 260° C. 4.11 S1.16 S3.35-(3,4-dichloro-phenyl)-3-pyridin-2-yl-7- 409.2 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine mp 188° C. 4.12 S1.7 S3.35-(4-trifluoromethyl-phenyl)-3-pyridin-2- 409.2 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 202° C. a]pyrimidine 4.13 S1.6S3.1 5-(3-trifluoromethyl-phenyl)-3-pyridin-3- 409.2 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 171° C. a]pyrimidine 4.14 S1.7S3.1 5-(4-trifluoromethyl-phenyl)-3-pyridin-3- 409.2 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 163° C. a]pyrimidine 4.15 S1.7S3.2 5-(4-trifluoromethyl-phenyl)-3-pyridin-4- 409.2 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 261° C. a]pyrimidine 4.16 S1.6S3.2 5-(3-trifluoromethyl-phenyl)-3-pyridin-4- 409.2 [(M + H)⁺]yl-7-trifluoromethyl-pyrazolo[1,5- mp 241° C. a]pyrimidine 4.17 S1.18S3.2 5-(3-fluoro-4-trifluoromethyl-phenyl)-3- 427.0 [(M + H)⁺]pyridin-4-yl-7-trifluoromethyl- mp 262° C. pyrazolo[1,5-a]pyrimidine4.18 S1.18 S3.1 5-(3-fluoro-4-trifluoromethyl-phenyl)-3- 427.0 [(M +H)⁺] pyridin-3-yl-7-trifluoromethyl- mp 162° C.pyrazolo[1,5-a]pyrimidine 4.19 S1.17 S3.45-(4-chloro-phenyl)-3-(2,6-dimethyl- 403.2 [(M + H)⁺]pyridin-4-yl)-7-trifluoromethyl- mp 256° C. pyrazolo[1,5-a]pyrimidine4.20 S1.15 S3.4 5-(4-chloro-3-methyl-phenyl)-3-(2,6- 417.2 [(M + H)⁺]dimethyl-pyridin-4-yl)-7-trifluoromethyl- mp 254° C.pyrazolo[1,5-a]pyrimidine 4.21 S1.14 S3.45-(3-chloro-4-fluoro-phenyl)-3-(2,6- 421.1 [(M + H)⁺]dimethyl-pyridin-4-yl)-7-trifluoromethyl- mp 271° C.pyrazolo[1,5-a]pyrimidine 4.22 S1.16 S3.45-(3,4-dichloro-phenyl)-3-(2,6-dimethyl- 437.1 [(M + H)⁺]pyridin-4-yl)-7-trifluoromethyl- mp 281° C. pyrazolo[1,5-a]pyrimidine4.23 S1.7 S3.4 5-(4-trifluoromethyl-phenyl)-3-(2,6- 437.2 [(M + H)⁺]dimethyl-pyridin-4-yl)-7-trifluoromethyl- mp 257° C.pyrazolo[1,5-a]pyrimidine 4.24 S1.6 S3.45-(3-trifluoromethyl-phenyl)-3-(2,6- 437.2 [(M + H)⁺]dimethyl-pyridin-4-yl)-7-trifluoromethyl- mp 236° C.pyrazolo[1,5-a]pyrimidine 4.25 S1.18 S3.45-(3-fluoro-4-trifluoromethyl-phenyl)-3- 455.0 [(M + H)⁺](2,6-dimethyl-pyridin-4-yl)-7- mp 245° C.trifluoromethyl-pyrazolo[1,5-a]pyrimidine 4.26 S1.21 S3.15-(4-methyl-3-trifluoromethyl-phenyl)-3- 423.2 [(M + H)⁺]pyridin-3-yl-7-trifluoromethyl- mp 182° C. pyrazolo[1,5-a]pyrimidine4.27 S1.21 S3.2 5-(4-methyl-3-trifluoromethyl-phenyl)-3- 423.1 [(M +H)⁺] pyridin-4-yl-7-trifluoromethyl- mp 218° C.pyrazolo[1,5-a]pyrimidine 4.28 S1.21 S3.45-(4-methyl-3-trifluoromethyl-phenyl)-3- 451.2 [(M + H)⁺](2,6-dimethyl-pyridin-4-yl)-7- mp 258° C.trifluoromethyl-pyrazolo[1,5-a]pyrimidine 4.29 S1.17 S3.55-(4-chloro-phenyl)-3-(2-methyl-pyridin-4- 389.1 [(M + H)⁺]yl)-7-trifluoromethyl-pyrazolo[1,5- mp 220° C. a]pyrimidine 4.30 S1.15S3.5 5-(4-chloro-3-methyl-phenyl)-3-(2-methyl- 403.5 [(M + H)⁺]pyridin-4-yl)-7-trifluoromethyl- mp 240° C. pyrazolo[1,5-a]pyrimidine4.31 S1.14 S3.5 5-(3-chloro-4-fluoro-phenyl)-3-(2-methyl- 407.3 [(M +H)⁺] pyridin-4-yl)-7-trifluoromethyl- mp 292° C.pyrazolo[1,5-a]pyrimidine 4.32 S1.16 S3.55-(3,4-dichloro-phenyl)-3-(2-methyl- 423.0 [(M + H)⁺]pyridin-4-yl)-7-trifluoromethyl- mp 275° C. pyrazolo[1,5-a]pyrimidine4.33 S1.7 S3.5 5-(4-trifluoromethyl-phenyl)-3-(2-methyl- 423.0 [(M +H)⁺] pyridin-4-yl)-7-trifluoromethyl- mp 243° C.pyrazolo[1,5-a]pyrimidine 4.34 S1.6 S3.55-(3-trifluoromethyl-phenyl)-3-(2-methyl- 423.3 [(M + H)⁺]pyridin-4-yl)-7-trifluoromethyl- mp 232° C. pyrazolo[1,5-a]pyrimidine4.35 S1.18 S3.5 5-(3-fluoro-4-trifluoromethyl-phenyl)-3-(2- 441.5 [(M +H)⁺] methyl-pyridin-4-yl)-7-trifluoromethyl- mp 250° C.pyrazolo[1,5-a]pyrimidine 4.36 S1.19 S3.15-(3-methyl-4-trifluoromethyl-phenyl)-3- 423.3 [(M + H)⁺]pyridin-3-yl-7-trifluoromethyl- mp 177° C. pyrazolo[1,5-a]pyrimidine4.37 S1.19 S3.2 5-(3-methyl-4-trifluoromethyl-phenyl)-3- 423.3 [(M +H)⁺] pyridin-4-yl-7-trifluoromethyl- mp 227° C.pyrazolo[1,5-a]pyrimidine 4.38 S1.19 S3.45-(3-methyl-4-trifluoromethyl-phenyl)-3- 451.5 [(M + H)⁺](2,6-dimethyl-pyridin-4-yl)-7- mp 253° C.trifluoromethyl-pyrazolo[1,5-a]pyrimidine 4.39 S1.19 S3.55-(3-methyl-4-trifluoromethyl-phenyl)-3- 437.5 [(M + H)⁺](2-methyl-pyridin-4-yl)-7-trifluoromethyl- mp 237° C.pyrazolo[1,5-a]pyrimidine 4.40 S1.22 S3.15-(4-ethoxy-3-trifluoromethyl-phenyl)-3- 453.5 [(M + H)⁺]pyridin-3-yl-7-trifluoromethyl- mp 178° C. pyrazolo[1,5-a]pyrimidine4.41 S1.22 S3.2 5-(4-ethoxy-3-trifluoromethyl-phenyl)-3- 453.5 [(M +H)⁺] pyridin-4-yl-7-trifluoromethyl- mp 233° pyrazolo[1,5-a]pyrimidine4.42 S1.20 S3.1 5-(4-trifluoroethoxy-3-trifluoromethyl- 507.5 [(M + H)⁺]phenyl)-3-pyridin-3-yl-7-trifluoromethyl- mp 181° C.pyrazolo[1,5-a]pyrimidine 4.43 S1.20 S3.25-(4-trifluorothoxy-3-trifluoromethyl- 507.5 [(M + H)⁺]phenyl)-3-pyridin-4-yl-7-trifluoromethyl- mp 247° C.pyrazolo[1,5-a]pyrimidine 4.44 S1.22 S3.55-(4-ethoxy-3-trifluoromethyl-phenyl)-3- 467.2 [(M + H)⁺](2-methyl-pyridin-4-yl)-7-trifluoromethyl- mp 250° C.pyrazolo[1,5-a]pyrimidine 4.45 S1.20 S3.45-(4-trifluoroethoxy-3-trifluoromethyl- 535.5 [(M + H)⁺]phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7- mp 229° C.trifluoromethyl-pyrazolo[1,5-a]pyrimidine 4.46 S1.20 S3.55-(4-trifluoroethoxy-3-trifluoromethyl- 521.5 [(M + H)⁺]phenyl)-3-(2-methyl-pyridin-4-yl)-7- mp 210° C.trifluoromethyl-pyrazolo[1,5-a]pyrimidine 4.47 S1.26 S3.25-(3-Ethoxy-4-trifluoromethyl-phenyl)-3- MS (ISP)pyridin-4-yl-7-trifluoromethyl- 453.1 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine mp 251° C. 4.48 S1.26 S3.43-(2,6-Dimethyl-pyridin-4-yl)-5-(3-ethoxy- MS (ISP)4-trifluoromethyl-phenyl)-7- 481.4 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine mp 257° C. 4.49 S1.26 S3.55-(3-Ethoxy-4-trifluoromethyl-phenyl)-3- MS (ISP)(2-methyl-pyridin-4-yl)-7-trifluoromethyl- 467.4 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine mp 226° C. 4.50 S1.27 S3.23-Pyridin-4-yl-5-[3-(2,2,2-trifluoro- MS (ISP)ethoxy)-4-trifluoromethyl-phenyl]-7- 507.4 [(M + H)⁺]trifluoromethyl-pyrazolo[1,5-a]pyrimidine mp 251° C. 4.51 S1.27 S3.43-(2,6-Dimethyl-pyridin-4-yl)-5-[3-(2,2,2- MS (ISP)trifluoro-ethoxy)-4-trifluoromethyl- 535.4 [(M + H)⁺]phenyl]-7-trifluoromethyl-pyrazolo[1,5- mp 245° C. a]pyrimidine 4.52S1.27 S3.5 3-(2-Methyl-pyridin-4-yl)-5-[3-(2,2,2- MS (ISP)trifluoro-ethoxy)-4-trifluoromethyl- 521.4 [(M + H)⁺]phenyl]-7-trifluoromethyl-pyrazolo[1,5- mp 201° C. a]pyrimidine 4.53S1.28 S3.2 5-(3,4-Bis-trifluoromethyl-phenyl)-3- MS (ISP)pyridin-4-yl-7-trifluoromethyl- 477.2 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine. Yellow solid. mp 209° C. 4.54 S1.28 S3.55-(3,4-Bis-trifluoromethyl-phenyl)-3-(2- MS (ISP)methyl-pyridin-4-yl)-7-trifluoromethyl- 491.3 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine mp 223° C. 4.55 S1.29 S3.25-(4-Bromo-phenyl)-3-pyridin-4-yl-7- MS (ISP)trifluoromethyl-pyrazolo[1,5-a]pyrimidine 421.2 [(M + H)⁺] mp 289° C.4.56 S1.29 S3.5 5-(4-Bromo-phenyl)-3-(2-methyl-pyridin- MS (ISP)4-yl)-7-trifluoromethyl-pyrazolo[1,5- 433.3 [(M + H)⁺] a]pyrimidine mp226° C. 4.57 S1.29 S3.4 5-(4-Bromo-phenyl)-3-(2,6-dimethyl- MS (ISP)pyridin-4-yl)-7-trifluoromethyl- 447.2 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine mp 258° C. 4.58 S1.30 S3.25-(4-Methoxy-phenyl)-3-pyridin-4-yl-7- MS (ISP)trifluoromethyl-pyrazolo[1,5-a]pyrimidine 371.2 [(M + H)⁺] mp 244° C.

EXAMPLE 4.15-(4-Chloro-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251mg, 1.0 mmol), prepared from commercially available4-chloro-acetophenone according to general procedure A, and3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure Byielded the title compound as a yellow solid (306 mg, 82%). MS (ISP)375.3 [(M+H)⁺]; mp 188° C.

EXAMPLE 4.25-(4-Chloro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125mg, 0.5 mmol), prepared from commercially available4-chloro-acetophenone according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 9.5 mmol) according to general procedure Byielded the title compound as a yellow solid (135 mg, 72%). MS (ISP)375.3 [(M+H)⁺]; mp 274° C.

EXAMPLE 4.35-(4-Chloro-3-methyl-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (265 mg,1.0 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure Byielded the title compound as a yellow solid (274 mg, 70%). MS (ISP)375.3 [(M+H)⁺]; mp 193° C.

EXAMPLE 4.45-(4-Chloro-3-methyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg,0.5 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (145 mg, 75%). MS (ISP)389.2 [(M+H)⁺]; mp 247° C.

EXAMPLE 4.55-(4-Chloro-3-methyl-phenyl)-3-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (265 mg,1.0 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure Byielded the title compound as a yellow solid (270 mg, 69%). MS (ISP)389.2 [(M+H)⁺]; mp 183° C.

EXAMPLE 4.65-(3-Chloro-4-fluoro-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg,1.0 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure Byielded the title compound as a yellow solid (270 mg, 69%). MS (ISP)393.1 [(M+H)⁺]; mp 190° C.

EXAMPLE 4.75-(3-Chloro-4-fluoro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg,0.5 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (82 mg, 42%). MS (ISP)393.1 [(M+H)⁺]; mp 265° C.

EXAMPLE 4.85-(3-Chloro-4-fluoro-phenyl)-3-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg,1.0 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure Byielded the title compound as a yellow solid (279 mg, 71%). MS (ISP)393.1 [(M+H)⁺]; mp 197° C.

EXAMPLE 4.95-(3,4-Dichloro-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(285 mg, 1.0 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure Byielded the title compound as a light yellow solid (274 mg, 67%). MS(ISP) 409.1 [(M+H)⁺]; mp 224° C.

EXAMPLE 4.105-(3,4-Dichloro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(285 mg, 1.0 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure Byielded the title compound as a yellow solid (94 mg, 46%). MS (ISP)409.2 [(M+H)⁺]; mp 260° C.

EXAMPLE 4.115-(3,4-Dichloro-phenyl)-3-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(285 mg, 1.0 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure Byielded the title compound as a yellow solid (223 mg, 55%). MS (ISP)409.2 [(M+H)⁺]; mp 188° C.

EXAMPLE 4.125-(4-Trifluoromethyl-phenyl)-3-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (145 mg, 71%). MS (ISP)409.2 [(M+H)⁺]; mp 202° C.

EXAMPLE 4.135-(3-Trifluoromethyl-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (126 mg, 62%). MS (ISP)409.2 [(M+H)⁺]; mp 171° C.

EXAMPLE 4.145-(4-Trifluoromethyl-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (142 mg, 70%). MS (ISP)409.2 [(M+H)⁺]; mp 163° C.

EXAMPLE 4.155-(4-Trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (93 mg, 46%). MS (ISP)409.2 [(M+H)⁺]; mp 261° C.

EXAMPLE 4.165-(3-Trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (95 mg, 47%). MS (ISP)409.2 [(M+H)⁺]; mp 241° C.

EXAMPLE 4.175-(3-Fluoro-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(151 mg, 0.5 mmol), prepared from commercially available3-fluoro-4-trifluoromethyl -acetophenone according to general procedureA, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; preparedfrom 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (92 mg, 43%). MS (ISP)427.0 [(M+H)⁺]; mp 262° C.

EXAMPLE 4.185-(3-Fluoro-4-trifluoromethyl-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(151 mg, 0.5 mmol), prepared from commercially available3-fluoro-4-trifluoromethyl -acetophenone according to general procedureA, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; preparedfrom 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (135 mg, 63%). MS (ISP)427.0 [(M+H)⁺]; mp 162° C.

EXAMPLE 4.195-(4-Chloro-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125mg, 0.5 mmol), prepared from commercially available4-chloro-acetophenone according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see partsynthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (95 mg,47%). MS (ISP) 403.2 [(M+H)⁺]; mp 256° C.

EXAMPLE 4.205-(4-Chloro-3-methyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg,0.5 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, see part synthesis ofamino-pyrazole derivatives] (94 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (95 mg, 46%).MS (ISP) 417.2 [(M+H)⁺]; mp 254° C.

EXAMPLE 4.215-(3-Chloro-4-fluoro-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg,0.5 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see partsynthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (97 mg,46%). MS (ISP) 421.1 [(M+H)⁺]; mp 271° C.

EXAMPLE 4.225-(3,4-Dichloro-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(143 mg, 0.5 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see partsynthesis of amino -pyrazole derivatives] (94 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (106mg, 48%). MS (ISP) 437.1 [(M+H)⁺]; mp 281° C.

EXAMPLE 4.235-(4-Trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see partsynthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (102mg, 47%). MS (ISP) 437.2 [(M+H)⁺]; mp 257° C.

EXAMPLE 4.245-(3-Trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see partsynthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (99 mg,45%). MS (ISP) 437.2 [(M+H)⁺]; mp 236° C.

EXAMPLE 4.255-(3-Fluoro-4-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(151 mg, 0.5 mmol), prepared from commercially available3-fluoro-4-trifluoromethyl-acetophenone according to general procedureA, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see partsynthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (46 mg,20%). MS (ISP) 455.0 [(M+H)⁺]; mp 245° C.

EXAMPLE 4.265-(4-Methyl-3-trifluoromethyl-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from4-methyl-3-trifluoromethyl-acetophenone according to general procedureA, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; preparedfrom 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (160 mg, 76%). MS (ISP)423.2 [(M+H)⁺]; mp 182° C.

EXAMPLE 4.275-(4-Methyl-3-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from4-methyl-3-trifluoromethyl-acetophenone according to general procedureA, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; preparedfrom 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (122 mg, 58%). MS (ISP)423.1 [(M+H)⁺]; mp 218° C.

EXAMPLE 4.285-(4-Methyl-3-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from4-methyl-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, see part synthesis ofamino-pyrazole derivatives] (94 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (114 mg, 51%).MS (ISP) 451.2 [(M+H)⁺]; mp 258° C.

EXAMPLE 4.295-(4-Chloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125mg, 0.5 mmol), prepared from commercially available4-chloro-acetophenone according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (84 mg, 43%).MS (ISP) 389.1 [(M+H)⁺]; mp 220° C.

EXAMPLE 4.305-(4-Chloro-3-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg,0.5 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (97 mg, 48%).MS (ISP) 403.5 [(M+H)⁺]; mp 240° C.

EXAMPLE 4.315-(3-Chloro-4-fluoro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg,0.5 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (86 mg, 42%).MS (ISP) 407.3 [(M+H)⁺]; mp 292° C.

EXAMPLE 4.325-(3,4-Dichloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(143 mg, 0.5 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (100 mg, 47%).MS (ISP) 423.0 [(M+H)⁺]; mp 275° C.

EXAMPLE 4.335-(4-Trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5, mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (111 mg, 53%).MS (ISP) 423.0 [(M+H)⁺]; mp 243° C.

EXAMPLE 4.345-(3-Trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (108 mg, 51%).MS (ISP) 423.3 [(M+H)⁺]; mp 232° C.

EXAMPLE 4.355-(3-Fluoro-4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(151 mg, 0.5 mmol), prepared from commercially available3-fluoro-4-trifluoromethyl-acetophenone according to general procedureA, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (85 mg, 39%).MS (ISP) 441.5 [(M+H)⁺]; mp 250° C.

EXAMPLE 4.365-(3-Methyl-4-trifluoromethyl-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from3-cyanomethyl -pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as an orange solid (116 mg, 55%). MS (ISP)423.3 [(M+H)⁺]; mp 177° C.

EXAMPLE 4.375-(3-Methyl-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl -pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (104 mg, 49%). MS (ISP)423.3 [(M+H)⁺]; mp 227° C.

EXAMPLE 4.385-(3-Methyl-4-trifluoromethyl-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see partsynthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (107mg, 48%). MS (ISP) 451.5 [(M+H)⁺]; mp 253° C.

EXAMPLE 4.395-(3-Methyl-4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (113 mg, 52%).MS (ISP) 437.5 [(M+H)⁺]; mp 237° C.

EXAMPLE 4.405-(4-Ethoxy-3-trifluoromethyl-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from3-cyanomethyl -pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (155 mg, 68%). MS (ISP)453.5 [(M+H)⁺]; mp 178° C.

EXAMPLE 4.415-(4-Ethoxy-3-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(1164 mg, 0.5 mmol), prepared from4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (128 mg, 57%). MS (ISP)453.5 [(M+H)⁺]; mp 233° C.

EXAMPLE 4.425-(4-Trifluoroethoxy-3-trifluoromethyl-phenyl)-3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from 4-trifluoroethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) accordingto general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No.40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg.Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (174mg, 69%). MS (ISP) 507.5 [(M+H)⁺]; mp 181° C.

EXAMPLE 4.435-[4-(2,2,2-Trifluorothoxy)-3-trifluoromethyl-phenyl]-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: seepart acetophenone derivatives) according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (139 mg, 55%). MS (ISP)507.5 [(M+H)⁺]; mp 247° C.

EXAMPLE 4.445-(4-Ethoxy-3-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (145 mg, 62%).MS (ISP) 467.2 [(M+H)⁺]; mp 250° C.

EXAMPLE 4.455-[4-(2,2,2-Trifluoroethoxy)-3-trifluoromethyl-phenyl]-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: seepart acetophenone derivatives) according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see partsynthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (165mg, 62%). MS (ISP) 535.5 [(M+H)⁺]; mp 229° C.

EXAMPLE 4.465-[4-(2,2,2-Trifluoroethoxy)-3-trifluoromethyl-phenyl]-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: seepart acetophenone derivatives) according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis ofamino-pyrazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (176 mg, 68%).MS (ISP) 521.5 [(M+H)⁺]; mp 210° C.

EXAMPLE 4.475-(3-Ethoxy-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (108 mg, 48%). MS (ISP)453.1 [(M+H)⁺]; mp 251° C.

EXAMPLE 4.483-(2,6-Dimethyl-pyridin-4-yl)-5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, as describedin Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (94 mg, 0.5 mmol)according to general procedure B yielded the title compound as a yellowsolid (120 mg, 50%). MS (ISP) 481.4 [(M+H)⁺]; mp 257° C.

EXAMPLE 4.495-(3-Ethoxy-4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem.Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (113 mg, 49%).MS (ISP) 467.4 [(M+H)⁺]; mp 226° C.

EXAMPLE 4.503-Pyridin-4-yl-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: seepart acetophenone derivatives) according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (127 mg, 50%). MS (ISP)507.4 [(M+H)⁺]; mp 251° C.

EXAMPLE 4.513-(2,6-Dimethyl-pyridin-4-yl)-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: seepart acetophenone derivatives) according to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, as describedin Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (94 mg, 0.5 mmol)according to general procedure B yielded the title compound as a yellowsolid (139 mg, 52%). MS (ISP) 535.4 [(M+H)⁺]; mp 245° C.

EXAMPLE 4.523-(2-Methyl-pyridin-4-yl)-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: seepart acetophenone derivatives) according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem.Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (140 mg, 54%).MS (ISP) 521.4 [(M+H)⁺]; mp 201° C.

EXAMPLE 4.535-(3,4-Bis-trifluoromethyl-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (176mg, 0.5 mmol), prepared from commercially available3,4-bis-trifluoromethyl-acetophenone [CAS No. 129604-25-7] according togeneral procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No.216661-87-9; prepared from 4-cyanomethyl-pyridine as described inBioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol)according to general procedure B yielded the title compound as a yellowsolid (83 mg, 35%). Yellow solid. MS (ISP) 477.2 [(M+H)⁺]; mp 209° C.

EXAMPLE 4.545-(3,4-Bis-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (176mg, 0.5 mmol), prepared from commercially available3,4-bis-trifluoromethyl-acetophenone [CAS No. 129604-25-7] according togeneral procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole[prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg.Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a yellow solid (93 mg,38%). MS (ISP) 491.3 [(M+H)⁺]; mp 223° C.

EXAMPLE 4.555-(4-Bromo-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg,0.5 mmol), prepared from commercially available 4-bromo-acetophenoneaccording to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole[CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as describedin Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol)according to general procedure B yielded the title compound as a yellowsolid (79 mg, 38%). MS (ISP) 421.2 [(M+H)⁺]; mp 289° C.

EXAMPLE 4.565-(4-Bromo-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg,0.5 mmol), prepared from commercially available 4-bromo-acetophenoneaccording to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem.Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (94 mg, 43%).MS (ISP) 433.3 [(M+H)⁺]; mp 226° C.

EXAMPLE 4.575-(4-Bromo-phenyl)-3-(2,6-dimethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg,0.5 mmol), prepared from commercially available 4-bromo-acetophenoneaccording to general procedure A, and3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, as describedin Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (94 mg, 0.5 mmol)according to general procedure B yielded the title compound as a yellowsolid (93 mg, 42%). MS (ISP) 447.2 [(M+H)⁺]; mp 258° C.

EXAMPLE 4.585-(4-Methoxy-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Reaction of 1-(4-methoxy-phenyl)-4,4,4-trifluoro-butane-1,3-dione (123mg, 0.5 mmol), prepared from commercially available4-methoxy-acetophenone according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (110 mg, 59%). MS (ISP)371.2 [(M+H)⁺]; mp 244° C.

EXAMPLE 5 Preparation ofphenyl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitriles andpyridinyl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitriles

A stirred mixture of commercially available 4-amino-5-cyano-1H-imidazole(1 eq.) and a 1-phenyl-4,4,4-trifluoro-butane-1,3-dione or1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione (1 eq.), preparedaccording to general procedure A, in acetic acid was heated under refluxconditions for 3.5 h. The reaction mixture was evaporated and theproduct was isolated by column chromatography (heptane/ethyl acetate)and further purified by crystallization. If the product precipitatesduring the reaction it can be isolated by filtration and furtherpurified by crystallization.

Ex. dione compound name MS (ISP)/mp 5.1 S1.232-phenyl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine- 289.0 [(M + H)⁺]8-carbonitrile mp 202° C. 5.2 S1.172-(4-chloro-phenyl)-4-trifluoromethyl-imidazo[1,5- 323.1 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 205° C. 5.3 S1.12-(3-chloro-phenyl)-4-trifluoromethyl-imidazo[1,5- 323.1 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 221° C. 5.4 S1.22-(4-methyl-phenyl)-4-trifluoromethyl-imidazo[1,5- 303.1 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 197° C. 5.5 S1.242-(4-methoxy-phenyl)-4-trifluoromethyl- 319.1 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 192° C. 5.6 S1.32-(2-chloro-phenyl)-4-trifluoromethyl-imidazo[1,5- 323.1 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 180° C. 5.7 S1.42-(2,4-dichloro-phenyl)-4-trifluoromethyl- 357.0 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 139° C. 5.8 S1.252-(2-methyl-phenyl)-4-trifluoromethyl-imidazo[1,5- 303.0 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 151° C. 5.9 S1.52-(3-methyl-phenyl)-4-trifluoromethyl-imidazo[1,5- 302.9 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 202° C. 5.10 S1.22-(4-trifluoromethyl-phenyl)-4-trifluoromethyl- 357.0 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 236° C. 5.11 S1.62-(3-trifluoromethyl-phenyl)-4-trifluoromethyl- 357.0 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 202° C. 5.12 S1.85-(3-fluoro-phenyl)-7-trifluoromethyl-imidazo[1,5- 307.0 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 210° C. 5.13 S1.95-(4-fluoro-phenyl)-7-trifluoromethyl-imidazo[1,5- 307.0 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 206° C. 5.14 S1.105-(2,4-difluoro-phenyl)-7-trifluoromethyl- 325.2 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 169° C. 5.15 S1.115-(2-fluoro-phenyl)-7-trifluoromethyl-imidazo[1,5- 307.1 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 147° C. 5.16 S1.125-(3,4-difluoro-phenyl)-7-trifluoromethyl- 325.2 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 187° C. 5.17 S1.135-(4-fluoro-3-trifluoromethyl-phenyl)-7- 375.3 [(M + H)⁺]trifluoromethyl-imidazo[1,5-a]pyrimidine-8- mp 207° C. carbonitrile 5.18S1.14 5-(3-chloro-4-fluoro-phenyl)-7-trifluoromethyl- 341.1 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 195° C. 5.19 S1.155-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl- 337.1 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 238° C. 5.20 S1.165-(3,4-dichloro-phenyl)-7-trifluoromethyl- 357.2 [(M + H)⁺]imidazo[1,5-a]pyrimidine-8-carbonitrile mp 219° C. 5.21 S1.185-(3-fluoro-4-trifluoromethyl-phenyl)-7- 375.0 [(M + H)⁺]trifluoromethyl-imidazo[1,5-a]pyrimidine-8- mp 210° C. carbonitrile 5.22S1.21 2-(4-methyl-3-trifluoromethyl-phenyl)-4- 371.1 [(M + H)⁺]trifluoromethyl-imidazo[1,5-a]pyrimidine-8- mp 220° C. carbonitrile 5.23S1.19 2-(3-methyl-4-trifluoromethyl-phenyl)-4- 371.1 [(M + H)⁺]trifluoromethyl-imidazo[1,5-a]pyrimidine-8- mp 217° C. carbonitrile 5.24S1.20 2-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4- 453.0 [M⁺]trifluoromethyl-imidazo[1,5-a]pyrimidine-8- mp 189° C. carbonitrile 5.25S2.1 2-pyridin-2-yl-4-trifluoromethyl-imidazo[1,5- 289.9 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 205° C. 5.26 S2.22-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5- 290.1 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 222° C. 5.27 S2.32-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5- 289.8 [(M + H)⁺]a]pyrimidine-8-carbonitrile mp 254° C.

EXAMPLE 5.12-Phenyl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-phenyl-4,4,4-trifluoro-butane-1,3-dione (216 mg, 1.0mmol), prepared from commercially available acetophenone according togeneral procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol)according to general procedure B yielded the title compound as a yellowsolid (107 mg, 37%). MS (ISP) 289.0 [(M+H)⁺]; mp 202° C.

EXAMPLE 5.22-(4-Chloro-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251mg, 1.0 mmol), prepared from commercially available4-chloro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (124 mg, 38%).MS (ISP) 323.1 [(M+H)⁺]; mp 205° C.

EXAMPLE 5.32-(3-Chloro-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(3-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251mg, 1.0 mmol), prepared from commercially available3-chloro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (133 mg, 41%).MS (ISP) 323.1 [(M+H)⁺]; mp 221° C.

EXAMPLE 5.42-(4-Methyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(4-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230mg, 1.0 mmol), prepared from commercially available4-methyl-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (133 mg, 44%).MS (ISP) 303.1 [(M+H)⁺]; mp 197° C.

EXAMPLE 5.52-(4-Methoxy-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(4-methoxy-phenyl)-4,4,4-trifluoro-butane-1,3-dione (246mg, 1.0 mmol), prepared from commercially available4-methoxy-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (125 mg, 39%).MS (ISP) 319.1 [(M+H)⁺]; mp 192° C.

EXAMPLE 5.62-(2-Chloro-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(2-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251mg, 1.0 mmol), prepared from commercially available2-chloro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (55 mg, 17%).MS (ISP) 323.1 [(M+H)⁺]; mp 180° C.

EXAMPLE 5.72-(2,4-Dichloro-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(2,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(285 mg, 1.0 mmol), prepared from commercially available2,4-dichloro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (43 mg, 12%).MS (ISP) 357.0 [(M+H)⁺]; mp 139° C.

EXAMPLE 5.82-(2-Methyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(2-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230mg, 1.0 mmol), prepared from commercially available2-methyl-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (19 mg, 6%). MS(ISP) 303.0 [(M+H)⁺]; mp 151° C.

EXAMPLE 5.92-(3-Methyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230mg, 1.0 mmol), prepared from commercially available3-methyl-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (161 mg, 53%).MS (ISP) 302.9 [(M+H)⁺]; mp 202° C.

EXAMPLE 5.102-(4-Trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg,1.0 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (151 mg, 42%).MS (ISP) 357.0 [(M+H)⁺]; mp 236° C.

EXAMPLE 5.112-(3-Trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg,1.0 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (125 mg, 35%).MS (ISP) 357.0 [(M+H)⁺]; mp 202° C.

EXAMPLE 5.125-(3-Fluoro-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(3-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234mg, 1.0 mmol), prepared from commercially available3-fluoro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (128 mg, 42%).MS (ISP) 307.0 [(M+H)⁺]; mp 210° C.

EXAMPLE 5.135-(4-Fluoro-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234mg, 1.0 mmol), prepared from commercially available4-fluoro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (119 mg, 39%).MS (ISP) 307.0 [(M+H)⁺]; mp 206° C.

EXAMPLE 5.145-(2,4-Difluoro-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(2,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(252 mg, 1.0 mmol), prepared from commercially available2,4-difluoro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (75 mg, 23%).MS (ISP) 325.2 [(M+H)⁺]; mp 169° C.

EXAMPLE 5.155-(2-Fluoro-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(2-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234mg, 1.0 mmol), prepared from commercially available2-fluoro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (99 mg, 32%).MS (ISP) 307.1 [(M+H)⁺]; mp 147° C.

EXAMPLE 5.165-(3,4-Difluoro-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(3,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(252 mg, 1.0 mmol), prepared from commercially available3,4-difluoro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (107 mg, 33%).MS (ISP) 325.2 [(M+H)⁺]; mp 187° C.

EXAMPLE 5.175-(4-Fluoro-3-trifluoromethyl-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(302 mg, 1.0 mmol), prepared from commercially available4-fluoro-3-trifluoromethyl-acetophenone according to general procedureA, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according togeneral procedure B yielded the title compound as a yellow solid (141mg, 38%). MS (ISP) 375.3 [(M+H)⁺]; mp 207° C.

EXAMPLE 5.185-(3-Chloro-4-fluoro-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg,1.0 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (120 mg, 35%).MS (ISP) 341.1 [(M+H)⁺]; mp 195° C.

EXAMPLE 5.195-(4-Chloro-3-methyl-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (265 mg,1.0 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (171 mg, 51%).MS (ISP) 337.1 [(M+H)⁺]; mp 238° C.

EXAMPLE 5.205-(3,4-Dichloro-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(285 mg, 1.0 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (161 mg, 45%).MS (ISP) 357.2 [(M+H)⁺]; mp 219° C.

EXAMPLE 5.215-(3-Fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(302 mg, 1.0 mmol), prepared from commercially available3-fluoro-4-trifluoromethyl-acetophenone according to general procedureA, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according togeneral procedure B yielded the title compound as a yellow solid (110mg, 29%). MS (ISP) 375.0 [(M+H)⁺]; mp 210° C.

EXAMPLE 5.222-(4-Methyl-3-trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(298 mg, 1.0 mmol), prepared from4-methyl-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to generalprocedure B yielded the title compound as a yellow solid (143 mg, 39%).MS (ISP) 371.1 [(M+H)⁺]; mp 220° C.

EXAMPLE 5.232-(3-Methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(224 mg, 0.75 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and4-amino-5-cyano-1H-imidazole (81 mg, 0.75 mmol) according to generalprocedure B yielded the title compound as a yellow solid (131 mg, 47%).MS (ISP) 371.1 [(M+H)⁺]; mp 217° C.

EXAMPLE 5.242-(4-Trifluoroethoxy-3-trifluoromethyl-phenyl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(382 mg, 1.0 mmol), prepared from 4-trifluoroethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) accordingto general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0mmol) according to general procedure B yielded the title compound as ayellow solid (182 mg, 40%). MS (ISP) 453.0 [M⁺]; mp 189° C.

EXAMPLE 5.252-Pyridin-2-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0mmol), prepared from commercially available 2-acetylpyridine accordingto general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0mmol) according to general procedure B yielded the title compound as ayellow solid (135 mg, 47%). MS (ISP) 289.9 [(M+H)⁺]; mp 205° C.

EXAMPLE 5.262-Pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-pyridin-3-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0mmol), prepared from commercially available 3-acetylpyridine accordingto general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0mmol) according to general procedure B yielded the title compound as ayellow solid (37 mg, 13%). MS (ISP) 290.1 [(M+H)⁺]; mp 222° C.

EXAMPLE 5.272-Pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine-8-carbonitrile

Reaction of 1-pyridin-4-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0mmol), prepared from commercially available 4-acetylpyridine accordingto general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0mmol) according to general procedure B yielded the title compound as ayellow solid (77 mg, 27%). MS (ISP) 289.8 [(M+H)⁺]; mp 254° C.

EXAMPLE 65-phenyl)-3-(2-hydroxymethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidines

(General Procedure C)

General Procedure C:

To a stirred solution of a5-phenyl-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine prepared according to general procedure B(example 4) in dichloromethane MeOH and 3-chloro-perbenzoic acid areadded at RT. The solution is stirred at RT for about 17 h, sat. NaHCO₃solution and dichloromethane is added and the mixture was stirred forabout 30 min. The organic layer is separated, washed with a Na₂S₂O₃solution, sat. NaHCO₃ solution, brine and dried (Mg₂SO₄). Evaporation ofthe solvent yields a crude5-phenyl-3-(2-methyl-1-oxo-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidinecompound as a solid, which can be used without further purification.

b) A stirred mixture of a5-phenyl-3-(2-methyl-1-oxo-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidinecompound and acetic acid anhydride is refluxed for about 30 min, pouredinto sat. NaHCO₃ solution and extracted with dichloromethane (e.g. 3times 20 ml). The combined organic layers is washed with brine and dried(MgSO₄). Purification of the crude product by column chromatography onsilica gel (ethyl acetate/hexane 1:1) yields a4-[5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-ylmethylacetate compound as a solid.

c) To a stirred solution of said4-[5-phenyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-ylmethylacetate compound in MeOH is added at RT NaOMe. The reaction mixture isstirred for about 17 h, poured into water and extracted withdichloromethane (e.g. 3 times 40 ml). The combined organic layers iswashed with brine, dried (MgSO₄) and evaporated. The crude product canbe further purified by column chromatography on silica gel (e.g. ethylacetate) to yield the title compounds as a solid.

Pyrimidine Ex. compound compound name MS (ISP)/mp 6.1 4.335-(4-Trifluoromethyl-phenyl)-3-(2-hydroxymethyl- MS (ISP)pyridin-4-yl)-7-trifluoromethyl- 439.3 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine mp 102° C. 6.2 4.395-(3-Methyl-4-trifluoromethyl-phenyl)-3-(2- MS (ISP)hydroxymethyl-pyridin-4-yl)-7-trifluoromethyl- 453.4 [(M + H)⁺]pyrazolo[1,5-a]pyrimidine mp 231° C. 6.3 4.30{4-[5-(4-Chloro-3-methyl-phenyl)-7- MS (ISP)trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]- 419.3 [(M + H)⁺]pyridin-2-yl}-methanol mp 220° C. 6.4 4.32{4-[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl- MS (ISP)pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-yl}- 439.2 [(M + H)⁺] methanolmp 233° C.

EXAMPLE 6.15-(4-Trifluoromethyl-phenyl)-3-(2-hydroxymethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

To a stirred solution of5-(4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine(0.15 g, 0.36 mmol, synthesis: see example 89) in dichloromethane (3.5ml) was added at room temperature MeOH (1 ml) and 3-chloro-perbenzoicacid (70%, 0.10 mg, 0.41 mmol). The yellow solution was stirred at RTfor 17 h, sat. NaHCO₃ solution (10 ml) and dichloromethane (10 ml) wasadded and the mixture was stirred for 30 min. The organic layer wasseparated, washed with 10% Na₂S₂O₃ solution (10 ml), sat. NaHCO₃solution (20 ml), brine (30 ml) and dried (Mg₂SO₄). Evaporation of thesolvent yielded crude5-(4-trifluoromethyl-phenyl)-3-(2-methyl-1-oxo-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidineas an orange solid (0.16 g), which was used without furtherpurification.

b) A stirred mixture of5-(4-trifluoromethyl-phenyl)-3-(2-methyl-1-oxo-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine(0.15 g, 0.33 mmol) and acetic acid anhydride (1 ml) was refluxed for 30min, poured into sat. NaHCO₃ solution (20 ml) and extracted withdichloromethane (3 times 20 ml). The combined organic layers were washedwith brine (50 ml) and dried (MgSO₄). Purification of the crude productby column chromatography on silica gel (ethyl acetate/hexane 1:1)yielded4-[5-(4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-ylmethyl acetate (0.16 g, 99%) as a brown solid.

c) To a stirred solution of4-[5-(4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-ylmethyl acetate (0.16 g, 0.33mmol) in MeOH (1 ml) was added at room temperature NaOMe (5.4M in MeOH,0.2 ml). The reaction mixture was stirred for 17 h, poured into water(40 ml) and extracted with dichloromethane (3 times 40 ml). The combinedorganic layers were washed with brine (100 ml), dried (MgSO₄) andevaporated. The crude product was further purified by columnchromatography on silica gel (ethyl acetate) to yield the title compound(112 mg, 78%) as an orange solid. MS (ISP) 439.3 [(M+H)⁺]; mp 2102° C.

EXAMPLE 6.25-(3-Methyl-4-trifluoromethyl-phenyl)-3-(2-hydroxymethyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine

Transformation of5-(3-methyl-4-trifluoromethyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine(0.34 g, 0.78 mmol, synthesis: see example 96) according to the generalmethod of example 108 yielded the title compound (80 mg, 23%) as anorange solid. MS (ISP) 453.4 [(M+H)⁺]; mp 231° C.

EXAMPLE 6.3{4-[5-(4-Chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-yl}-methanol

Transformation of5-(4-chlor-3-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine(0.40 g, 1.0 mmol, synthesis: see example 86) according to the generalmethod of example 108 yielded the title compound (140 mg, 33%) as anorange solid. MS (ISP) 419.3 [(M+H)⁺]; mp 220° C.

EXAMPLE 6.4{4-[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-yl}-methanol

Transformation of5-(3,4-dichloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine(0.43 g, 1.0 mmol, synthesis: see example 88) according to the generalmethod of example 108 yielded the title compound (73 mg, 17%) as anorange solid. MS (ISP) 439.2 [(M+H)⁺]; mp 233° C.

EXAMPLE 75-(4-Chloro-3-methyl-phenyl)-3-(2-methyl-1-oxy-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine(compound no. 7.1)

To a stirred solution of5-(4-chloro-3-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (0.50 g, 1.24 mmol) indichloromethane (12 ml) was added at RT MeOH (3 ml) and3-chloro-perbenzoic acid (70%, 0.36 mg, 1.44 mmol). The orange solutionwas stirred at RT for 17 h, sat. NaHCO₃ solution (75 ml) anddichloromethane (50 ml) was added and the mixture was stirred for 30min. The organic layer was separated, washed with 10% Na₂S₂O₃ solution(60 ml), sat. NaHCO₃ solution (60 ml), brine (100 ml) and dried(Mg₂SO₄). Evaporation of the solvent and crystallization yielded thetitle compound (0.51 g, 99%) as an orange solid. MS (ISP) 418.1 [M⁺]; mp279° C.

Oxidation of5-(3,4-dichloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (0.63 g, 1.49 mmol) according to the aboveprocedure yielded5-(3,4-dichloro-phenyl)-3-(2-methyl-1-oxy-pyridin-4-yl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidinecompound no. 7.2 (0.63 g, 96%) as an orange solid. MS (ISP) 438.0 [M⁺];mp 287° C.

EXAMPLE 8 Preparation of5-phenyl-3-pyridinyl-7-trifluoromethyl-imidazol[1,5-a]pyrimidines

(General Procedure B)

Ex. dione compound name MS (ISP)/mp 8.1 S1.152-(4-Chloro-3-methyl-phenyl)-8-pyridin-3-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 289.3 [(M + H)⁺] mp 210° C. 8.2S1.17 2-(4-Chloro-phenyl)-8-pyridin-3-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 375.5 [(M + H)⁺] mp 206° C. 8.3S1.14 2-(3-Chloro-4-fluoro-phenyl)-8-pyridin-3-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 393.1 [(M + H)⁺] mp 188° C. 8.4S1.16 2-(4-Dichloro-phenyl)-8-pyridin-3-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 409.4 [(M + H)⁺] mp 226° C. 8.5S1.6 8-Pyridin-3-yl-4-trifluoromethyl-2-(3- MS (ISP)trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine 409.4 [(M + H)⁺] mp194° C. 8.6 S1.7 8-Pyridin-3-yl-4-trifluoromethyl-2-(4- MS (ISP)trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine 409.4 [(M + H)⁺] mp231° C. 8.7 S1.21 2-(4-Methyl-3-trifluoromethyl-phenyl)-8-pyridin-3- MS(ISP) yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 423.1 [(M + H)⁺] mp236° C. 8.8 S1.19 2-(3-Methyl-4-trifluoromethyl-phenyl)-8-pyridin-3- MS(ISP) yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 423.3 [(M + H)⁺] mp173° C. 8.9 S1.17 2-(4-Chloro-phenyl)-8-pyridin-4-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 375.5 [(M + H)⁺] mp 290° C.8.10 S1.15 2-(4-Chloro-3-methyl-phenyl)-8-pyridin-4-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 389.3 [(M + H)⁺] mp 254° C.8.11 S1.14 2-(3-Chloro-4-fluoro-phenyl)-8-pyridin-4-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 393.1 [(M + H)⁺] mp 266° C.8.12 S1.16 2-(4-Dichloro-phenyl)-8-pyridin-4-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 409.3 [(M + H)⁺] mp 262° C.8.13 S1.6 8-Pyridin-4-yl-4-trifluoromethyl-2-(3- MS (ISP)trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine 409.4 [(M + H)⁺] mp258° C. 8.14 S1.7 8-Pyridin-4-yl-4-trifluoromethyl-2-(4- MS (ISP)trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine 409.4 [(M + H)⁺] mp240° C. 8.15 S1.19 2-(3-Fluoro-4-trifluoromethyl-phenyl)-8-pyridin-4- MS(ISP) yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 427.4.0 [(M + H)⁺]mp 267° C. 8.16 S1.21 2-(4-Methyl-3-trifluoromethyl-phenyl)-8-pyridin-4-MS (ISP) yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 423.3 [(M + H)⁺]mp 222° C. 8.17 S1.22 2-(4-Ethoxy-3-trifluoromethyl-phenyl)-8-pyridin-4-MS (ISP) yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 453.5.0 [(M +H)⁺] mp 244° C. 8.18 S1.208-Pyridin-4-yl-2-[4-(2,2,2-trifluoro-ethoxy)-3- MS (ISP)trifluoromethyl-phenyl]-4-trifluoromethyl- 507.5 [(M + H)⁺]imidazo[1,5-a]pyrimidine mp 269° C. 8.19 S1.192-(3-Methyl-4-trifluoromethyl-phenyl)-8-pyridin-4- MS (ISP)yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 422.1 [(M + H)⁺] mp 225°C. 8.20 S1.17 2-(4-Chloro-phenyl)-8-(2-methyl-pyridin-4-yl)-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 389.2 [(M + H)⁺] mp 232° C.8.21 S1.15 2-(4-Chloro-3-methyl-phenyl)-8-(2-methyl-pyridin- MS (ISP)4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 403.4 [(M + H)⁺] mp246° C. 8.22 S1.14 2-(3-Chloro-4-fluoro-phenyl)-8-(2-methyl-pyridin- MS(ISP) 4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 407.3 [(M + H)⁺]mp 255° C. 8.23 S1.16 2-(4-Dichloro-phenyl)-8-(2-methyl-pyridin-4-yl)-4-MS (ISP) trifluoromethyl-imidazo[1,5-a]pyrimidine 423.2 [(M + H)⁺] mp271° C. 8.24 S1.7 8-(2-Methyl-pyridin-4-yl)-4-trifluoromethyl-2-(4- MS(ISP) trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine 423.2 [(M + H)⁺]mp 257° C. 8.25 S1.6 8-(2-Methyl-pyridin-4-yl)-4-trifluoromethyl-2-(3-MS (ISP) trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine 423.2 [(M +H)⁺] mp 234° C. 8.26 S1.182-(3-Fluoro-4-trifluoromethyl-phenyl)-8-(2-methyl- MS (ISP)pyridin-4-yl-4-trifluoromethyl-imidazo[1,5- 441.2 [(M + H)⁺]a]pyrimidine mp 252° C. 8.27 S1.222-(4-Ethoxy-3-trifluoromethyl-phenyl)-8-(2-methyl- MS (ISP)pyridin-4-yl-4-trifluoromethyl-imidazo[1,5- 467.4 [(M + H)⁺]a]pyrimidine mp 249° C. 8.28 S1.208-(2-Methyl-pyridin-4-yl-2-[4-(2,2,2-trifluoro- MS (ISP)ethoxy)-3-trifluoromethyl-phenyl]-4- 521.4 [(M + H)⁺]trifluoromethyl-imidazo[1,5-a]pyrimidine mp 219° C. 8.29 S1.192-(3-Methyl-4-trifluoromethyl-phenyl)-8-(2-methyl- MS (ISP)pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5- 437.4 [(M + H)⁺]a]pyrimidine mp 243° C. 8.30 S1.262-(3-Ethoxy-4-trifluoromethyl-phenyl)-8-pyridin-4- MS (ISP)yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine 453.4 [(M + H)⁺] mp 212°C. 8.31 S1.26 2-(3-Ethoxy-4-trifluoromethyl-phenyl)-8-(2-methyl- MS(ISP) pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5- 467.2 [(M + H)⁺]a]pyrimidine mp 177° C. 8.32 S1.278-Pyridin-4-yl-2-[3-(2,2,2-trifluoro-ethoxy)-4- MS (ISP)trifluoromethyl-phenyl]-4-trifluoromethyl- 507.4 [(M + H)⁺]imidazo[1,5-a]pyrimidine mp 233° C. 8.33 S1.278-(2-Methyl-pyridin-4-yl)-2-[3-(2,2,2-trifluoro- MS (ISP)ethoxy)-4-trifluoromethyl-phenyl]-4- 521.3 [(M + H)⁺]trifluoromethyl-imidazo[1,5-a]pyrimidine mp 189° C. 8.34 S1.282-(3,4-Bis-trifluoromethyl-phenyl)-8-pyridin-4-yl-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 477.2 [(M + H)⁺] mp 211° C.8.35 S1.28 2-(3,4-Bis-trifluoromethyl-phenyl)-8-(2-methyl- MS (ISP)pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5- 491.3 [(M + H)⁺]a]pyrimidine mp 218° C. 8.36 S1.292-(4-Bromo-phenyl)-8-(2-methyl-pyridin-4-yl)-4- MS (ISP)trifluoromethyl-imidazo[1,5-a]pyrimidine 435.3 [(M + H)⁺] mp 249° C.

EXAMPLE 8.12-(4-Chloro-3-methyl-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg,0.5 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride [synthesis: seepart amino-imidazole derivatives] (117 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a red solid (43 mg,22%). MS (ISP) 289.3 [(M+H)⁺]; mp 210° C.

EXAMPLE 8.22-(4-Chloro-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125mg, 0.5 mmol), prepared from commercially available4-chloro-acetophenone according to general procedure A, and2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride [synthesis: seepart amino-imidazole derivatives] (117 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as an orange solid (43mg, 23%). MS (ISP) 375.5 [(M+H)⁺]; mp 206° C.

EXAMPLE 8.32-(3-Chloro-4-fluoro-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg,0.5 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride [synthesis: seepart amino-imidazole derivatives] (117 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as an orange solid (62mg, 32%). Orange solid. MS (ISP) 393.1 [(M+H)⁺]; mp 188° C.

EXAMPLE 8.42-(4-Dichloro-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(143 mg, 0.5 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride [synthesis: seepart amino-imidazole derivatives] (117 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as an orange solid (66mg, 32%). Red solid. MS (ISP) 409.4 [(M+H)⁺]; mp 226° C.

EXAMPLE 8.58-Pyridin-3-yl-4-trifluoromethyl-2-(3-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg,1.0 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride [synthesis: seepart amino-imidazole derivatives] (233 mg, 1.0 mmol) according togeneral procedure B yielded the title compound as a red solid (54 mg,13%). MS (ISP) 409.4 [(M+H)⁺]; mp 194° C.

EXAMPLE 8.68-Pyridin-3-yl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg,1.0 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride [synthesis: seepart amino-imidazole derivatives] (233 mg, 1.0 mmol) according togeneral procedure B yielded the title compound as an orange solid (73mg, 18%). MS (ISP) 409.4 [(M+H)⁺]; mp 231° C.

EXAMPLE 8.72-(4-Methyl-3-trifluoromethyl-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from4-methyl-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride [synthesis: seepart amino-imidazole derivatives] (117 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as a red solid (84 mg,40%). MS (ISP) 423.1 [(M+H)⁺]; mp 236° C.

EXAMPLE 8.82-(3-Methyl-4-trifluoromethyl-phenyl)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(3-pyridinyl)-1H-imidazole dihydrochloride [synthesis: seepart amino-imidazole derivatives] (117 mg, 0.5 mmol) according togeneral procedure B yielded the title compound as an orange solid (103mg, 49%). MS (ISP) 423.3 [(M+H)⁺]; mp 173° C.

EXAMPLE 8.92-(4-Chloro-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125mg, 0.5 mmol), prepared from commercially available4-chloro-acetophenone according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (44 mg, 23%).MS (ISP) 375.5 [(M+H)⁺]; mp 290° C.

EXAMPLE 8.102-(4-Chloro-3-methyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg,0.5 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (98 mg, 50%).MS (ISP) 389.3 [(M+H)⁺]; mp 254° C.

EXAMPLE 8.112-(3-Chloro-4-fluoro-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg,0.5 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (84 mg, 43%).MS (ISP) 393.1 [(M+H)⁺]; mp 266° C.

EXAMPLE 8.122-(4-Dichloro-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(143 mg, 0.5 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (95 mg, 46%).MS (ISP) 409.3 [(M+H)⁺]; mp 262° C.

EXAMPLE 8.138-Pyridin-4-yl-4-trifluoromethyl-2-(3-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (100 mg, 49%).MS (ISP) 409.4 [(M+H)⁺]; mp 258° C.

EXAMPLE 8.148-Pyridin-4-yl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (88 mg, 43%).MS (ISP) 409.4 [(M+H)⁺]; mp 240° C.

EXAMPLE 8.152-(3-Fluoro-4-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(151 mg, 0.5 mmol), prepared from commercially available3-fluoro-4-trifluoromethyl -acetophenone according to general procedureA, and 2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (116 mg, 54%).MS (ISP) 427.4.0 [(M+H)⁺]; mp 267° C.

EXAMPLE 8.162-(4-Methyl-3-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from4-methyl-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (101 mg, 48%).MS (ISP) 423.3 [(M+H)⁺]; mp 222° C.

EXAMPLE 8.172-(4-Ethoxy-3-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (98 mg, 43%).MS (ISP) 453.5.0 [(M+H)⁺]; mp 244° C.

EXAMPLE 8.188-Pyridin-4-yl-2-[4-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-phenyl]-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-[4-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from4-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-acetophenone (synthesis:see part acetophenone derivatives) according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (111 mg, 44%).MS (ISP) 507.5 [(M+H)⁺]; mp 269° C.

EXAMPLE 8.192-(3-Methyl-4-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (93 mg, 44%).MS (ISP) 422.1 [(M+H)⁺]; mp 225° C.

EXAMPLE 8.202-(4-Chloro-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125mg, 0.5 mmol), prepared from commercially available4-chloro-acetophenone according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (46 mg, 24%).MS (ISP) 389.2 [(M+H)⁺]; mp 232° C.

EXAMPLE 8.212-(4-Chloro-3-methyl-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg,0.5 mmol), prepared from commercially available4-chloro-3-methyl-acetophenone according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (49 mg, 24%).MS (ISP) 403.4 [(M+H)⁺]; mp 246° C.

EXAMPLE 8.222-(3-Chloro-4-fluoro-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg,0.5 mmol), prepared from commercially available3-chloro-4-fluoro-acetophenone according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (52 mg, 26%).MS (ISP) 407.3 [(M+H)⁺]; mp 255° C.

EXAMPLE 8.232-(4-Dichloro-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione(143 mg, 0.5 mmol), prepared from commercially available3,4-dichloro-acetophenone according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (57 mg, 27%).MS (ISP) 423.2 [(M+H)⁺]; mp 271° C.

EXAMPLE 8.248-(2-Methyl-pyridin-4-yl)-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine

Reaction of1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (46 mg, 22%).MS (ISP) 423.2 [(M+H)⁺]; mp 257° C.

EXAMPLE 8.258-(2-Methyl-pyridin-4-yl)-4-trifluoromethyl-2-(3-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine

Reaction of1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg,0.5 mmol), prepared from commercially available3-trifluoromethyl-acetophenone according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (59 mg, 28%).MS (ISP) 423.2 [(M+H)⁺]; mp 234° C.

EXAMPLE 8.262-(3-Fluoro-4-trifluoromethyl-phenyl)-8-(2-methyl-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(151 mg, 0.5 mmol), prepared from commercially available3-fluoro-4-trifluoromethyl-acetophenone according to general procedureA, and 2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: seepart amino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a red solid (59 mg, 27%). MS(ISP) 441.2 [(M+H)⁺]; mp 252° C.

EXAMPLE 8.272-(4-Ethoxy-3-trifluoromethyl-phenyl)-8-(2-methyl-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (41 mg, 18%).MS (ISP) 467.4 [(M+H)⁺]; mp 249° C.

EXAMPLE 8.288-(2-Methyl-pyridin-4-yl-2-[4-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-phenyl]-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-[4-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from4-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-acetophenone (synthesis:see part acetophenone derivatives) according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (51 mg, 20%).Orange solid. MS (ISP) 521.4 [(M+H)⁺]; mp 219° C.

EXAMPLE 8.292-(3-Methyl-4-trifluoromethyl-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(149 mg, 0.5 mmol), prepared from3-methyl-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (44 mg, 20%).Orange solid. MS (ISP) 437.4 [(M+H)⁺]; mp 243° C.

EXAMPLE 8.302-(3-Ethoxy-4-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (70 mg, 31%).MS (ISP) 453.4 [(M+H)⁺]; mp 212° C.

EXAMPLE 8.312-(3-Ethoxy-4-trifluoromethyl-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione(164 mg, 0.5 mmol), prepared from3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see partacetophenone derivatives) according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (30 mg, 13%).MS (ISP) 467.2 [(M+H)⁺]; mp 177° C.

EXAMPLE 8.328-Pyridin-4-yl-2-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-acetophenone (synthesis:see part acetophenone derivatives) according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (84 mg, 33%).MS (ISP) 507.4 [(M+H)⁺]; mp 233° C.

EXAMPLE 8.338-(2-Methyl-pyridin-4-yl)-2-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione(191 mg, 0.5 mmol), prepared from3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-acetophenone (synthesis:see part acetophenone derivatives) according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (140 mg, 54%).MS (ISP) 521.3 [(M+H)⁺]; mp 189° C.

EXAMPLE 8.342-(3,4-Bis-trifluoromethyl-phenyl)-8-pyridin-4-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (176mg, 0.5 mmol), prepared from 3,4-bis-trifluoromethyl-acetophenone [CASNo. 129604-25-7] according to general procedure A, and2-amino-3-(4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (80 mg, 34%).MS (ISP) 477.2 [(M+H)⁺]; mp 211° C.

EXAMPLE 8.352-(3,4-Bis-trifluoromethyl-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (200mg, 0.57 mmol), prepared from 3,4-bis-trifluoromethyl-acetophenone [CASNo. 129604-25-7] according to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (99 mg, 0.57 mmol) according to generalprocedure B yielded the title compound as an orange solid (28 mg, 10%).Orange solid. MS (ISP) 491.3 [(M+H)⁺]; mp 218° C.

EXAMPLE 8.362-(4-Bromo-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromethyl-imidazo[1,5-a]pyrimidine

Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg,0.5 mmol), prepared from commercially available 4-bromo-acetophenoneaccording to general procedure A, and2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole [synthesis: see partamino-imidazole derivatives] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as an orange solid (42 mg, 19%).MS (ISP) 435.3 [(M+H)⁺]; mp 249° C.

EXAMPLE 9 Preparation of5-phenyl-3-pyridinyl-7-difluoromethyl-pyrazolo[1,5-a]pyrimidines

General Procedure B

A stirred mixture of a 3-amino-4-pyridinyl-pyrazole (1 eq.) and a1-phenyl-4,4,4-difluoro-butane-1,3-dione (1 eq.), prepared according togeneral procedure A, in acetic acid was heated under reflux conditionsfor about 3.5 h. The reaction mixture was evaporated and the product wasisolated by column chromatography (e.g. heptane/ethyl acetate) andfurther purified by crystallization. If the product precipitates duringthe reaction it can be isolated by filtration and further purified bycrystallization.

Ex. dione compound name MS (ISP)/mp 9.1 S1.77-Difluoromethyl-3-pyridin-4-yl-5-(4- MS (ISP)trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine 391.2 [(M + H)⁺] mp222° C. 9.2 S1.7 7-Difluoromethyl-3-(2-methyl-pyridin-4-yl)-5-(4- MS(ISP) trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine 405.4 [(M + H)⁺]mp 213° C. 9.3 S1.19 7-Difluoromethyl-5-(3-methyl-4-trifluoromethyl- MS(ISP) phenyl)-3-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine 405.4 [(M + H)⁺]mp 236° C. 9.4 S1.19 7-Difluoromethyl-3-(2-methyl-pyridin-4-yl)-5-(3- MS(ISP) methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5- 419.3 [(M + H)⁺]a]pyrimidine mp 221° C. 9.5 S1.307-Difluoromethyl-5-(4-methoxy-phenyl)-3-pyridin-4-yl- MS (ISP)pyrazolo[1,5-a]pyrimidine 353.2 [(M + H)⁺] mp 206° C.

EXAMPLE 9.17-Difluoromethyl-3-pyridin-4-yl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine

Reaction of 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione(133 mg, 0.5 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12(2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure Byielded the title compound as a yellow solid (130 mg, 67%). MS (ISP)391.2 [(M+H)⁺]; mp 222° C.

EXAMPLE 9.27-Difluoromethyl-3-(2-methyl-pyridin-4-yl)-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine

Reaction of 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione(133 mg, 0.5 mmol), prepared from commercially available4-trifluoromethyl-acetophenone according to general procedure A, and3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem.Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (159 mg, 79%).MS (ISP) 405.4 [(M+H)⁺]; mp 213° C.

EXAMPLE 9.37-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-3-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine

Reaction of4,4-difluoro-1-(3-methyl-4-trifluoromethyl-phenyl)-butane-1,3-dione (140mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone(synthesis: see part acetophenone derivatives) according to generalprocedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9;prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem.Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to generalprocedure B yielded the title compound as a yellow solid (140 mg, 69%).MS (ISP) 405.4 [(M+H)⁺]; mp 236° C.

EXAMPLE 9.47-Difluoromethyl-3-(2-methyl-pyridin-4-yl)-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine

Reaction of4,4-difluoro-1-(3-methyl-4-trifluoromethyl-phenyl)-butane-1,3-dione (140mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone(synthesis: see part acetophenone derivatives) according to generalprocedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [preparedfrom 4-cyanomethyl-2-methyl-pyridine, CAS No. 130138-46-4, as describedin Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol)according to general procedure B yielded the title compound as a yellowsolid (164 mg, 78%). MS (ISP) 419.3 [(M+H)⁺]; mp 221° C.

EXAMPLE 9.57-Difluoromethyl-5-(4-methoxy-phenyl)-3-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine

Reaction of 4,4-difluoro-1-(4-methoxy-phenyl)-butane-1,3-dione (114 mg,0.5 mmol), prepared from commercially available 4-methoxy-acetophenoneaccording to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole[CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as describedin Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol)according to general procedure B yielded the title compound as a yellowsolid (120 mg, 68%). MS (ISP) 353.2 [(M+H)⁺]; mp 206° C.

Compounds of formula I and their pharmaceutically acceptable salts(hereinafter: Pharmaceutical Compound) have pharmacological activity andare useful as pharmaceuticals. In particular, Pharmaceutical Compoundsexhibit metabotropic glutamate receptor antagonist activity. Inparticular, Pharmaceutical Compounds are active at the mGluR2 receptor.

The mGluR interaction of the Pharmaceutical Compounds may bedemonstrated, e.g. in an in vitro binding assay, e.g. as follows:

[³H]-LY354740 Binding on mGlu2 Transfected CHO Cell Membranes

Transfection and cell culture: cDNA encoding the rat mGlu2 receptorprotein in pBluescript II was subcloned into the eukaryotic expressionvector pcDNA I-amp from Invitrogen (NV Leek, The Netherlands). Thisvector construct (pcD1mGR2) was co-transfected with a psvNeo plasmidencoding the gene for neomycin resistance, into CHO cells by a modifiedcalcium phosphate method described by Chen & Okayama (1988). The cellswere maintained in Dulbecco's Modified Eagle medium with reducedL-glutamine (2 mM final concentration) and 10% dialyzed foetal calfserum from Gibco BRL (Basel, Switzerland). Selection was made in thepresence of G-418 (1000 μg/ml final). Clones were identified by reversetranscription of 5 μg total RNA, follow by PCR using mGlu2 receptorspecific primers 5′-atcactgcttgggtttctggcactg-3′ (SEQ ID NO: 1) and5′-agcatcactgtgggtggcataggagc-3′ (SEQ ID NO:2) in 60 mM Tris HCl (pH10), 15 mM (NH4)₂SO₄, 2 mM MgCl₂, 25 units/ml Taq Polymerase with 30cycles annealing at 60° C. for 1 min., extension at 72° C. for 30 s, and1 min. 95° C. denaturation.

Membrane preparation: Cells, cultured as above, were harvested andwashed three times with cold PBS and frozen at −80° C. The pellet wasresuspended in cold 20 mM HEPES-NaOH buffer containing 10 mM EDTA (pH7.4), and homogenized with a polytron (Kinematica, AG, Littau,Switzerland) for 10 s at 10 000 rpm. After centrifugation for 30 min. at4° C., the pellet was washed once with the same buffer, and once withcold 20 mM HEPES-NaOH buffer containing 0.1 mM EDTA, (pH 7.4). Proteincontent was measured using the Pierce method (Socochim, Lausanne,Switzerland) using bovine serum albumin as standard.

[³H]-LY354740 binding: After thawing, the membranes were resuspended incold 50 mM Tris-HCl buffer containing 2 mM MgCl₂ and 2 mM CaCl₂, (pH 7)(binding buffer). The final concentration of the membranes in the assayswas 25 μg protein/ml. Inhibition experiments were performed withmembranes incubated with 10 nM [³H]-LY354740 at room temperature, for 1hour, in the presence of various concentrations of the compound to betested. Following the incubations, membranes were filtered onto WhatmannGF/C glass fiber filters and washed 5 times with cold binding buffer.Non specific binding was measured in the presence of 10 μM DCG IV. Aftertransfer of the filters into plastic vials containing 10 ml ofUltima-gold scintillation fluid (Packard, Zürich, Switzerland), theradioactivity was measured by liquid scintillation in a Tri-Carb 2500 TRcounter (Packard, Zürich, Switzerland).

Data analysis: The inhibition curves were fitted with a four parameterlogistic equation giving IC₅₀ values, and Hill coefficients.

The compounds show activities, as measured in the above assay, of 5 μMor less, typically 0.5 μM or less, and ideally of 0.1 μM or less. Thebelow table shows exemplary K_(i) values:

Compound no. mGluR2 K_(i) [μM] Example mGluR2 K_(i) [μM] 1.13 0.043 4.350.045 1.19 0.032 4.43 0.048 2.2 0.072 4.9 0.047 3.2 0.076 5.20 0.0434.24 0.043 7.1 0.0439

Activity specifically as medicament in Alzheimer's disease may bedemonstrated in accordance with standard test methods, e.g. anasymptotic performance in an operant delayed match to position (DMTP)task, modified from the procedure originally published by Dunnett,Psychopharmacology (Berl) 87:357-63 (1985) [Higgins et al., Europ. J.Neuroscience 15:1827-1840 (2002); Higgins et al., Europ. J. Neuroscience15:911-922 (2002); Higgins et al., Neuropharmacology 44:324-241 (2003)].

Pharmaceutical Compounds and prodrugs thereof, e.g. esters, N-oxides,phosphate esters, glycoamide esters and glyceride conjugates, areaccordingly useful as mGluR antagonists, e.g. in the treatment orprevention of diseases and conditions in which activation of mGluR playsa role or is implicated. Such conditions include in particular acuteand/or chronic neurological disorders.

At present, eight different members of these mGluRs are known and ofthese some even have sub-types. On the basis of structural parameters,the different influences on the synthesis of secondary metabolites andthe different affinity to low-molecular weight chemical compounds, theseeight receptors can be sub-divided into three sub-groups: mGluR1 andmGluR5 belong to group I, mGluR2 and mGluR3 belong to group II andmGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the group IIcan be used for the treatment or prevention of acute and/or chronicneurological disorders.

Acute and/or chronic neurological disorders include psychosis,schizophrenia, Alzheimer's disease, cognitive disorders and memorydeficits like mild cognitive impairment, age-related cognitive decline,vascular dementia, Parkinsons's disease, memory impairment associatedwith depression or anxiety, Down's syndrome, stroke, traumatic braininjury, and attention deficit disorder. Other treatable indications arerestricted brain function caused by bypass operations or transplants,poor blood supply to the brain, spinal cord injuries, head injuries,hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Furthertreatable indications are acute and chronic pain, Huntington's chorea,amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eyeinjuries, retinopathy, idiopathic parkinsonism or parkinsonism caused bymedicaments as well as conditions which lead to glutamate-deficientfunctions, such as e.g. muscle spasms, convulsions, migraine, urinaryincontinence, nicotine addiction, psychotic episodes, opiate addiction,anxiety, vomiting, dyskinesia and depression.

In one embodiment, the acute and/or chronic neurological disorder isAlzheimer's disease. In another embodiment, the acute and/or chronicneurological disorder is mild cognitive impairment.

As used herein, a mammal in need of treatment of an acute and/or chronicneurological disorder means a mammal, e.g. a human that is sufferingfrom, or is at risk of suffering from, an acute and/or chronicneurological disorder.

As used herein, the terms “treat”, treating “and treatment”, and thelike, as applied to an acute and/or chronic neurological disorder, referto methods that slow, ameliorate, reduce or reverse such a disorder orany symptoms associated with said disorder, as currently afflicting thesubject, as well as methods that prevent such a disorder or any symptomsthereof, from occurring.

Pharmaceutical Compounds can be used as medicaments, e.g. in the form ofpharmaceutical compositions. The pharmaceutical compositions can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. However, the administration can also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

Pharmaceutical Compounds can be processed with pharmaceutically inert,inorganic or organic carriers for the production of pharmaceuticalcompositions. Lactose, corn starch or derivatives thereof, talc, stearicacid or its salts and the like can be used, e.g., as such carriers fortablets, coated tablets, dragées and hard gelatine capsules. Suitablecarriers for soft gelatine capsules are, e.g., vegetable oils, waxes,fats, semi-solid and liquid polyols and the like; depending on thenature of the active substance no carriers are, however, usuallyrequired in the case of soft gelatine capsules. Suitable carriers forthe production of solutions and syrups are, e.g., water, polyols,sucrose, invert sugar, glucose and the like. Adjuvants, such asalcohols, polyols, glycerol, vegetable oils and the like, can be usedfor aqueous injection solutions of water-soluble salts of compounds offormula I, but as a rule are not necessary. Suitable carriers forsuppositories are, e.g., natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical compositions may contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They may also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing Pharmaceutical Compound anda therapeutically inert excipient are also an object of the presentinvention, as is a process for the production of such medicaments whichcomprises bringing one or more Pharmaceutical Compound and, if desired,one or more other therapeutically valuable substances into a galenicaldosage form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, theeffective dosage for oral or parenteral administration is between0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred forall of the indications described. The daily dosage for an adult humanbeing weighing 70 kg accordingly lies between 0.7-1400 mg per day,preferably between 7 and 700 mg per day.

In accordance with the foregoing the present invention also provides:

-   (a) A pharmaceutical compound for use as a metabotropic glutamate    receptor antagonist, for example for use in any of the particular    indications as hereinbefore set forth;-   (b) A pharmaceutical composition comprising a pharmaceutical    compound as under (a) as active ingredient together with a    pharmaceutically acceptable diluent or carrier therefor;-   (c) A pharmaceutical composition for the treatment or prevention of    a disease or condition in which metabotropic glutamate receptor    activation plays a role or is implicated comprising a pharmaceutical    compound as under (a) and a carrier;-   (d) Use of a pharmaceutical compound as under (a) for the    manufacture of a medicament for the treatment or prevention of a    disease or condition in which metabotropic glutamate receptor    activation plays a role or is implicated;-   (e) A process for the preparation of a compound as under (a).

1. A compound of formula I

wherein A is ═C(R⁴)—, D is ═C(R⁵)—, E is ═C(R⁶)—, or one of A, D and Eis ═N—, L is ═C(H)—, M is ═N— Q is CF₃ of CHF₂, R¹ is selected from —CN,unsubstituted pyridinyl, pyridinyl substituted by (C₁-C₄)-alkyl,pyridinyl substituted by (C₁-C₄)-alkanol, and correspondingpyridine-N-oxide of unsubstituted pyridinyl, pyridinyl substituted by(C₁-C₄)-alkyl, pyridinyl substituted by (C₁-C₄)-alkanol, R² is selectedfrom hydrogen, halogen, (C₁-C₄)-alkyl and (C₃-C₆)-cycloalkyl, R³ isselected from hydrogen, halogen, (C₁-C₄)-alkyl and (C₃-C₆)-cycloalkyl,R⁴ is selected from hydrogen, halogen, unsubstituted (C₁-C₄)-alkyl,(C₁-C₄)-alkyl substituted by fluorine, unsubstituted (C₁-C₄)-alkoxy,(C₁-C₄)-alkoxy substituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyland (C₃-C₆)-cycloalkyl substituted by fluorine, R⁵ is selected fromhydrogen, halogen, unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkylsubstituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl substituted by fluorine, and R⁶ is hydrogen orhalogen or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1 wherein: A is ═C(R⁴)—, D is ═C(R⁵)—, E is ═C(R⁶)—,or one of A, D and E is ═N—, L is ═C(H)—, M is ═N— Q is CF₃, R¹ isselected from —CN, unsubstituted pyridinyl, pyridinyl substituted by(C₁-C₄)-alkyl and corresponding pyridine-N-oxide of pyridinylsubstituted by (C₁-C₄)-alkyl, R² is selected from hydrogen, halogen,(C₁-C₄)-alkyl and (C₃-C₆)-cycloalkyl, R³ is selected from hydrogen,halogen, (C₁-C₄)-alkyl and (C₃-C₆)-cycloalkyl, R⁴ is selected fromhydrogen, halogen, unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkylsubstituted by fluorine, unsubstituted (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxysubstituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl substituted by fluorine, R⁵ is selected fromhydrogen, halogen, unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkylsubstituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl substituted by fluorine, and R⁶ is hydrogen orhalogen or a pharmaceutically acceptable salt thereof.
 3. The compoundaccording to claim 1 wherein A is ═C(R⁴)—, wherein R⁴ is selected fromhydrogen, halogen, unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkylsubstituted by fluorine, unsubstituted (C₁-C₄)-alkoxy, (C₁-C₄)-alkoxysubstituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl substituted by fluorine.
 4. The compound according toclaim 3 wherein R⁴ is halogen.
 5. The compound according to claim 1wherein D is ═C(R⁵)—, wherein R⁵ is selected from hydrogen, halogen,unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine,unsubstituted (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl substituted byfluorine.
 6. The compound according to claim 5 wherein R⁵ is CF₃.
 7. Thecompound according to claim 1 wherein E is ═C(R⁶)—, wherein R⁶ ishydrogen or halogen.
 8. The compound according to claim 1 wherein R¹ is—CN.
 9. The compound according to claim 1 wherein R¹ is selected fromunsubstituted pyridinyl, pyridinyl substituted by (C₁-C₄)-alkyl andcorresponding pyridine-N-oxide of pyridinyl substituted by(C₁-C₄)-alkyl.
 10. The compound according to claim 9 wherein R¹ ispyridinyl.
 11. The compound according to claim 9 wherein R¹ is pyridinylsubstituted by (C₁-C₄)-alkyl.
 12. The compound according to claim 9wherein R¹ is pyridinyl substituted by methyl.
 13. The compoundaccording to claim 9 wherein R¹ is 2-methyl-pyridin-4-yl.
 14. Thecompound according to claim 1 wherein A is ═C(R⁴)—, wherein R⁴ isselected from hydrogen, halogen, unsubstituted (C₁-C₄)-alkyl or(C₁-C₄)-alkyl substituted by fluorine, unsubstituted (C₁-C₄)-alkoxy,(C₁-C₄)-alkoxy substituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyland (C₃-C₆)-cycloalkyl substituted by fluorine, D is ═C(R⁵)—, wherein R⁵is selected from hydrogen, halogen, unsubstituted (C₁-C₄)-alkyl,(C₁-C₄)-alkyl substituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyland (C₃-C₆)-cycloalkyl substituted by fluorine, E is ═C(R⁶)—, wherein R⁶is hydrogen or halogen, L is ═C(H)—, M is ═N—, R¹ is selected from —CN,unsubstituted pyridinyl, pyridinyl substituted by (C₁-C₄)-alkyl, andcorresponding pyridine-N-oxide of pyridinyl substituted by(C₁-C₄)-alkyl, R² is selected from hydrogen, halogen, (C₁-C₄)-alkyl and(C₃-C₆)-cycloalkyl, R³ is selected from hydrogen, halogen, (C₁-C₄)-alkyland (C₃-C₆)-cycloalkyl.
 15. The compound according to claim 1 wherein Ais ═C(R⁴)—, wherein R⁴ is selected from hydrogen, halogen, unsubstituted(C₁-C₄)-alkyl, (C₁-C₄)-alkyl substituted by fluorine, unsubstituted(C₁-C₄)-alkoxy and (C₁-C₄)-alkoxy substituted by fluorine, D is ═C(R⁵)—,wherein R⁵ is selected from hydrogen, halogen, unsubstituted(C₁-C₄)-alkyl and (C₁-C₄)-alkyl substituted by fluorine, E is ═C(R⁶)—,wherein R⁶ is hydrogen or halogen, L is ═C(H)—, M is ═N—, R¹ is selectedfrom —CN, unsubstituted pyridinyl, pyridinyl substituted by(C₁-C₄)-alkyl and corresponding pyridine-N-oxide of pyridinylsubstituted by (C₁-C₄)-alkyl, R² is selected from hydrogen, halogen and(C₁-C₄)-alkyl, and R³ is selected from hydrogen, halogen and(C₁-C₄)-alkyl.
 16. A pharmaceutical composition comprising a compound offormula I

wherein A is ═C(R⁴)—, D is ═C(R⁵)—, E is ═C(R⁶)—, or one of A, D and Eis ═N—, L is ═C(H)—, M is ═N—, Q is CF₃ of CHF₂, R¹ is selected from—CN, unsubstituted pyridinyl, pyridinyl substituted by (C₁-C₄)-alkyl,pyridinyl substituted by (C₁-C₄)-alkanol, and correspondingpyridine-N-oxide of unsubstituted pyridinyl, pyridinyl substituted by(C₁-C₄)-alkyl, pyridinyl substituted by (C₁-C₄)-alkanol, R² is selectedfrom hydrogen, halogen, (C₁-C₄)-alkyl and (C₃-C₆)-cycloalkyl, R³ isselected from hydrogen, halogen, (C₁-C₄)-alkyl and (C₃-C₆)-cycloalkyl,R⁴ is selected from hydrogen, halogen, unsubstituted (C₁-C₄)-alkyl,(C₁-C₄)-alkyl substituted by fluorine, unsubstituted (C₁-C₄)-alkoxy,(C₁-C₄)-alkoxy substituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyland (C₃-C₆)-cycloalkyl substituted by fluorine, R⁵ is selected fromhydrogen, halogen, unsubstituted (C₁-C₄)-alkyl, (C₁-C₄)-alkylsubstituted by fluorine, unsubstituted (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl substituted by fluorine, and R⁶ is hydrogen orhalogen, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient thereof.